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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination with Atezolizumab or Placebo in Patients with HER2-Positive and PD-L1-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab- (+/- Pertuzumab) and Taxane-Based Therapy

    Summary
    EudraCT number
    		 2020-002818-41
    Trial protocol
    		 SI   DE   PT   NO   HU   FI   PL   FR   IT  
    Global end of trial date
    19 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2025
    First version publication date
    28 Jun 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MO42319
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04740918
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Jun 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the efficacy of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo in participants with human epidermal growth factor receptor 2 (HER2)-positive and programmed death-ligand 1 (PD-L1) -positive locally advanced (LABC) or metastatic breast cancer (MBC).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 31
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Philippines: 5
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Türkiye: 17
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Croatia: 2
    Worldwide total number of subjects
    96
    EEA total number of subjects
    21
    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)
    84
    From 65 to 84 years
    11
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 96 participants with HER2-positive and PD-L1-positive LABC or MBC took part in the study across 52 investigative sites in 19 countries from 07 June 2021 to 19 June 2024.

    Pre-assignment
    Screening details
    		 Participants were randomized in 1:1 ratio to receive trastuzumab emtansine + placebo (Arm 1) or trastuzumab emtansine + atezolizumab (Arm 2).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab Emtansine 3.6 mg + Placebo
    Arm description
    		 Participants received trastuzumab emtansine, 3.6 milligrams (mg), every 3 weeks (Q3W) as an intravenous (IV) infusion in combination with atezolizumab matching placebo, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab matching placebo dose, Q3W as IV infusion.

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    RO5304020
    Other name
    Kadcyla
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab Emtansine, 3.6 mg, Q3W as IV infusion.

    Arm title
    		 Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Arm description
    		 Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab, 1200 mg, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    RO5541267
    Other name
    Tecentriq, MPDL3280A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab, 1200 mg, Q3W as IV infusion.

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    RO5304020
    Other name
    Kadcyla
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab Emtansine, 3.6 mg, Q3W as IV infusion.

    Number of subjects in period 1
    		Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Started
    50
    46
    Completed
    0
    0
    Not completed
    50
    46
         Consent withdrawn by subject
    5
    4
         Death
    3
    6
         Study Terminated by Sponsor
    41
    32
         Lost to follow-up
    1
    3
         Progressive disease
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 milligrams (mg), every 3 weeks (Q3W) as an intravenous (IV) infusion in combination with atezolizumab matching placebo, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab, 1200 mg, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Reporting group values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg Total
    Number of subjects
    		 50 46 96
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.2 ( 11.7 ) 50.9 ( 10.0 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 50 46 96
        Male
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 4 11
        Not Hispanic or Latino
    		 42 39 81
        Unknown or Not Reported
    		 1 3 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 17 21 38
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 1 2
        White
    		 29 23 52
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 milligrams (mg), every 3 weeks (Q3W) as an intravenous (IV) infusion in combination with atezolizumab matching placebo, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab, 1200 mg, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Subject analysis set title
    Trastuzumab Emtansine 3.6 mg + Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab matching placebo, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Subject analysis set title
    Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab, 1200 mg, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Primary: Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Progression-Free Survival (PFS) as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented disease progression (PD), as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Median PFS was calculated using the Kaplan-Meier (KM) methodology. Data for participants without PD or death from any cause as of the data cut-off date were censored at the time of the last tumor assessment. ITT population included all participants who were randomized in the study, whether they received any study medication.
    End point type
    Primary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    50
    46
    Units: months
        median (confidence interval 95%)
    7.52 (6.18 to 10.94)
    8.61 (5.72 to 16.92)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.2876
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 1.28
    Notes
    [1] - Stratified Analysis: Local hormonal status (estrogen receptors (ER) and/or progesterone receptor (PgR) positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the first dose of study treatment to the time of death from any cause. Participants who are alive as of the data cut-off date of the analysis were censored at the last known date they were alive. Participants with no post-baseline information were censored at the date of randomization plus 1 day. Median OS was calculated using the KM methodology. ITT population included all participants who were randomized in the study, whether they received any study medication. 99999= median and 95% confidence interval (CI) was not estimable due to insufficient number of events. 9999=median and upper limit of 95% CI was not estimable due to insufficient number of events.
    End point type
    Primary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    50
    46
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    9999 (21.29 to 9999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.5151
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 6.43
    Notes
    [2] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR = percentage of participants with complete response (CR) or partial response (PR) on two consecutive assessments, at least 28 days apart, as determined by the investigator using RECIST v.1.1. CR = disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) having a reduction in short axis to <10 mm. PR = at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. Only participants with measurable disease at baseline were analyzed for this outcome measure. Participants without a post-baseline tumor assessment were considered non-responders. An estimate of the ORR and its 95% CI (Wilson score confidence interval) were calculated for each treatment arm. Subset ITT with measurable disease included all participants in the ITT with a measurable disease at baseline. ITT population included all participants who were randomized to the study, whether or not they received any study medication.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    49
    45
    Units: percentage of participants
        number (confidence interval 95%)
    49 (34.64 to 63.48)
    53.3 (38.04 to 68.07)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.724
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 2.7
    Notes
    [3] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was calculated for participants who had a best OR of CR/PR. DOR=time from first occurrence of documented OR until time of documented PD/death from any cause, whichever occurs first as determined by investigator assessment using RECIST. CR= disappearance of all target lesions or any pathological lymph nodes (whether target/non-target) having a reduction in short axis to <10 mm. PR=at least a 30% decrease in the SOD of target lesions, taking as reference baseline SOD. PD=at least a 20% increase in the SOD of target lesions, taking as reference smallest sum on the study including baseline (nadir). In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm. Median DOR was calculated using KM methodology. Subset ITT with measurable disease=all participants in the ITT with a measurable disease at baseline. Number analyzed=participants with OR i.e responders. 99999=upper limit of 95%CI was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    24
    24
    Units: months
        median (confidence interval 95%)
    8.21 (5.72 to 99999)
    15.57 (7.06 to 99999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.3531
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 1.61
    Notes
    [4] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Secondary: PFS in Participants With Baseline Brain Metastases as Determined by Investigator Assessment Using RECIST v1.1

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    End point title
    		 PFS in Participants With Baseline Brain Metastases as Determined by Investigator Assessment Using RECIST v1.1
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented PD, as determined by the investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Median PFS was calculated using the KM methodology. ITT with brain metastasis population included all participants in ITT with brain metastasis at randomization. 99999=upper limit of 95% CI was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    5
    4
    Units: months
        median (confidence interval 95%)
    7.69 (4.14 to 99999)
    4.78 (1.31 to 99999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.7175
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 6.81
    Notes
    [5] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Secondary: OS in Participants with Baseline Brain Metastases

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    End point title
    		 OS in Participants with Baseline Brain Metastases
    End point description
    OS is defined as the time from the first dose of study treatment to the time of death from any cause. Median OS was calculated using the KM methodology. ITT with brain metastasis population included all participants in ITT with brain metastasis at randomization. 99999= median and 95%CI was not estimable due to insufficient number of events. 9999= median and upper limit of 95%CI was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    5
    4
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    9999 (9.53 to 9999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    9
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.3173 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    999.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 9999
    Notes
    [6] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).
    [7] - The upper limit of the 95 % CI was not estimable due to the insufficient number of events.

    Secondary: Central Nervous System (CNS) PFS as Determined by Investigator Using RECIST v1.1 in Participants With Baseline CNS Metastases

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    End point title
    		 Central Nervous System (CNS) PFS as Determined by Investigator Using RECIST v1.1 in Participants With Baseline CNS Metastases
    End point description
    CNS PFS=time from randomization to first occurrence of documented CNS PD/first occurrence of symptomatic CNS disease as determined by investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD = at least a 20% increase in SOD of target lesions, taking as reference the smallest sum in study, including baseline, in addition to relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm. Median PFS was calculated using KM methodology. Participants who experienced non-CNS PD at time of analysis were censored at date of this progression. Participants who experienced no PD & were alive at time of analysis were censored at date of their last post-baseline tumor assessment or, if they had no post-baseline tumor assessment, on date of randomization+1 day. ITT with CNS metastasis population=all participants in ITT with CNS metastasis at randomization. 99999=upper limit of 95% CI was not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    7
    4
    Units: months
        median (confidence interval 95%)
    10.41 (4.11 to 99999)
    9.53 (1.31 to 99999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.8658
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 8.6
    Notes
    [8] - Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs) [9]
    End point description
    An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Safety evaluable population included all participants who received at least one full or partial dose of study drug. One participant randomized to Trastuzumab Emtansine + Placebo moved to Trastuzumab Emtansine + Atezolizumab 1200 mg. Hence, has been represented in the later arm for safety analysis.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: All analysis was descriptive only and no formal hypothesis testing was done.
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    49
    47
    Units: percentage of participants
        number (not applicable)
    93.9
    97.9
    No statistical analyses for this end point

    Secondary: CNS PFS as Determined by Investigator Using RECIST v1.1 in Participants Without Baseline CNS Metastases

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    End point title
    		 CNS PFS as Determined by Investigator Using RECIST v1.1 in Participants Without Baseline CNS Metastases
    End point description
    CNS PFS=time from randomization to first occurrence of documented CNS PD/first occurrence of symptomatic CNS disease as determined by investigator according to RECIST v1.1 or death from any cause whichever occurs first. PD=at least a 20% increase in SOD of target lesions, taking as reference the smallest sum in study, including baseline, in addition to relative increase of 20%, sum must also demonstrate an absolute increase of ≥5 mm. Participants who experienced non-CNS PD at time of analysis were censored at date of this progression. Participants who experienced no PD & were alive at time of analysis were censored at last post-baseline (PB) tumor assessment or on date of randomization+1 day (if no PB data). ITT without CNS metastases at baseline population=all participants in ITT without CNS metastasis at baseline. 9999=median & 95% CI were not estimable due to insufficient number of events. 999=median & upper limit of 95% CI were not estimable due to insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    43
    42
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    999 (21.29 to 999)
    Statistical analysis title
    		 Atezolizumab vs Placebo
    Statistical analysis description
    Stratified Analysis: Local hormonal status (ER and/or PgR positive vs. ER and PgR negative/unknown) and Disease status (visceral metastasis without brain metastasis vs. non-visceral metastasis only without brain metastasis [including locally advanced disease] vs. Brain metastasis).
    Comparison groups
    Trastuzumab Emtansine 3.6 mg + Placebo v Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8407
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 4.99

    Other pre-specified: Mean Absolute Scores in Physical Function (PF), Role Function (RF) and Global Health Status (GHS/QoL) Scores Measured Using European Organization for Research and Treatment of Cancer (EORTC QLQ-C30)

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    End point title
    		 Mean Absolute Scores in Physical Function (PF), Role Function (RF) and Global Health Status (GHS/QoL) Scores Measured Using European Organization for Research and Treatment of Cancer (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30 consists of 30 questions that assess five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The PF scale has 5 questions about participant’s PF and daily activities (strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves, or using the toilet). The RF scale has 2 questions about work/daily activities and hobbies/leisurely activities. The PF and RF are scored on a 4-point scale (1=Not at All to 4=Very Much). The GHS/QoL are scored on a 7-point scale (1=Very Poor to 7=Excellent). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level and better QoL, functioning/support.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [10] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [11] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: PFS as Determined by a Blinded Independent Central Review (BICR) Committee Using RECIST v1.1

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    End point title
    		 PFS as Determined by a Blinded Independent Central Review (BICR) Committee Using RECIST v1.1
    End point description
    PFS was defined as the time from randomization to the first occurrence of documented PD, as determined by the BICR committee according to RECIST v1.1 or death from any cause whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum in the study, including baseline, in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. As prespecified in the latest protocol, following sponsor’s decision to prematurely terminate the study, analysis of PFS as determined by a BICR committee was not conducted.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [12] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [13] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Change From-Baseline in PF, RF and GHS/QoL Scores Measured Using EORTC QLQ-C30

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    End point title
    		 Change From-Baseline in PF, RF and GHS/QoL Scores Measured Using EORTC QLQ-C30
    End point description
    EORTC QLQ-C30 consists of 30 questions that assess five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).The PF scale has 5 questions about participant’s PF and daily activities (strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves, or using the toilet). The RF scale has 2 questions about work/daily activities and hobbies/leisurely activities. The PF and RF are scored on a 4-point scale (1=Not at All to 4=Very Much). The GHS/QoL are scored on a 7-point scale (1=Very Poor to 7=Excellent). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level and better QoL, functioning/support.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [14] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [15] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine

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    End point title
    		 Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine
    End point description
    As prespecified in the latest protocol, following sponsor’s decision to prematurely terminate the study, pharmacokinetic (PK) objectives and outcome measures were no longer applicable. Hence sample collection was stopped, and this outcome measure was not assessed or analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: nanograms/milliliters (ng/mL)
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [16] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [17] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants with Clinically Meaningful Deterioration in PF, RF and GHS/QoL Measured Using EORTC QLQ-C30

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    End point title
    		 Percentage of Participants with Clinically Meaningful Deterioration in PF, RF and GHS/QoL Measured Using EORTC QLQ-C30
    End point description
    EORTC QLQ-C30 consists of 30 questions that assess five aspects of participant functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, pain), GHS/QoL, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).The PF scale has 5 questions about participant’s PF and daily activities (strenuous activities, long walks, short walks, bed/chair rest & needing help with eating, dressing, washing themselves, or using the toilet). The RF scale has 2 questions about work/daily activities and hobbies/leisurely activities. The PF and RF are scored on a 4-point scale (1=Not at All to 4=Very Much). The GHS/QoL are scored on a 7-point scale (1=Very Poor to 7=Excellent). The obtained scores are linearly transformed to a score range of 0-100, where higher scores indicate a higher response level and better QoL, functioning/support.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: percentage of participants
    Notes
    [18] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [19] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Cmax of Atezolizumab

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    End point title
    		 Cmax of Atezolizumab
    End point description
    As prespecified in the latest protocol, following sponsor’s decision to prematurely terminate the study, PK objectives and outcome measures were no longer applicable. Hence sample collection was stopped, and this outcome measure was not assessed or analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [20] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [21] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants With Anti-Drug Antibodies (ADAs) to Trastuzumab Emtansine

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    End point title
    		 Percentage of Participants With Anti-Drug Antibodies (ADAs) to Trastuzumab Emtansine
    End point description
    As prespecified in the latest protocol, following sponsor’s decision to prematurely terminate the study, immunogenicity objectives and outcome measures were no longer applicable. Hence sample collection was stopped, and this outcome measure was not assessed or analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: percentage of participants
    Notes
    [22] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [23] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Other pre-specified: Percentage of Participants With ADAs to Atezolizumab

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    End point title
    		 Percentage of Participants With ADAs to Atezolizumab
    End point description
    As prespecified in the latest protocol, following sponsor’s decision to prematurely terminate the study, immunogenicity objectives and outcome measures were no longer applicable. Hence sample collection was stopped, and this outcome measure was not assessed or analyzed.
    End point type
    Other pre-specified
    End point timeframe
    Up to 28 months
    End point values
    		 Trastuzumab Emtansine 3.6 mg + Placebo Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: percentage of participants
    Notes
    [24] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    [25] - Sponsor prematurely terminated the study, and hence analysis of this endpoint was not conducted.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 28 months
    Adverse event reporting additional description
    Safety evaluable population included all participants who received at least one full or partial dose of study drug. One participant randomized to Trastuzumab Emtansine + Placebo moved to Trastuzumab Emtansine + Atezolizumab 1200 mg. Hence, has been represented in the later arm for safety analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab, 1200 mg, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Reporting group title
    Trastuzumab Emtansine 3.6 mg + Placebo
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg, Q3W as an IV infusion in combination with atezolizumab matching placebo, Q3W as an IV infusion on Day 1 of each 21-day cycle until radiographic disease progression, intolerable toxicity, withdrawal of consent, death or study termination by the sponsor.

    Serious adverse events
    		 Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg Trastuzumab Emtansine 3.6 mg + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 47 (29.79%)
    9 / 49 (18.37%)
         number of deaths (all causes)
    6
    3
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Vascular device infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trastuzumab Emtansine 3.6 mg + Atezolizumab 1200 mg Trastuzumab Emtansine 3.6 mg + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 47 (97.87%)
    46 / 49 (93.88%)
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 49 (4.08%)
         occurrences all number
    3
    2
    Asthenia
         subjects affected / exposed
    7 / 47 (14.89%)
    4 / 49 (8.16%)
         occurrences all number
    9
    7
    Pyrexia
         subjects affected / exposed
    11 / 47 (23.40%)
    3 / 49 (6.12%)
         occurrences all number
    16
    4
    Fatigue
         subjects affected / exposed
    11 / 47 (23.40%)
    11 / 49 (22.45%)
         occurrences all number
    16
    15
    Influenza like illness
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 49 (6.12%)
         occurrences all number
    1
    4
    Oedema peripheral
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 49 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    7 / 47 (14.89%)
    7 / 49 (14.29%)
         occurrences all number
    8
    10
    Cough
         subjects affected / exposed
    5 / 47 (10.64%)
    7 / 49 (14.29%)
         occurrences all number
    6
    8
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 49 (4.08%)
         occurrences all number
    3
    2
    Insomnia
         subjects affected / exposed
    4 / 47 (8.51%)
    5 / 49 (10.20%)
         occurrences all number
    4
    6
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    10 / 47 (21.28%)
    2 / 49 (4.08%)
         occurrences all number
    28
    2
    Weight decreased
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 49 (6.12%)
         occurrences all number
    6
    3
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 49 (4.08%)
         occurrences all number
    16
    2
    Lipase increased
         subjects affected / exposed
    6 / 47 (12.77%)
    0 / 49 (0.00%)
         occurrences all number
    8
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    11 / 47 (23.40%)
    8 / 49 (16.33%)
         occurrences all number
    19
    14
    Blood bilirubin increased
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 49 (4.08%)
         occurrences all number
    23
    5
    White blood cell count decreased
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 49 (4.08%)
         occurrences all number
    32
    3
    Amylase increased
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    26 / 47 (55.32%)
    23 / 49 (46.94%)
         occurrences all number
    52
    33
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 47 (23.40%)
    4 / 49 (8.16%)
         occurrences all number
    19
    9
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 47 (23.40%)
    6 / 49 (12.24%)
         occurrences all number
    15
    8
    Blood cholesterol increased
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 49 (2.04%)
         occurrences all number
    5
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 47 (48.94%)
    15 / 49 (30.61%)
         occurrences all number
    52
    25
    Platelet count decreased
         subjects affected / exposed
    18 / 47 (38.30%)
    11 / 49 (22.45%)
         occurrences all number
    40
    21
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    5 / 47 (10.64%)
    5 / 49 (10.20%)
         occurrences all number
    5
    5
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    6 / 47 (12.77%)
    1 / 49 (2.04%)
         occurrences all number
    6
    1
    Headache
         subjects affected / exposed
    9 / 47 (19.15%)
    8 / 49 (16.33%)
         occurrences all number
    12
    17
    Dizziness
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 49 (6.12%)
         occurrences all number
    2
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    3 / 47 (6.38%)
    4 / 49 (8.16%)
         occurrences all number
    6
    8
    Leukopenia
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 49 (6.12%)
         occurrences all number
    3
    6
    Anaemia
         subjects affected / exposed
    20 / 47 (42.55%)
    10 / 49 (20.41%)
         occurrences all number
    36
    19
    Thrombocytopenia
         subjects affected / exposed
    12 / 47 (25.53%)
    14 / 49 (28.57%)
         occurrences all number
    20
    21
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 47 (34.04%)
    12 / 49 (24.49%)
         occurrences all number
    30
    18
    Diarrhoea
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 49 (8.16%)
         occurrences all number
    15
    4
    Abdominal pain
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 49 (2.04%)
         occurrences all number
    4
    1
    Vomiting
         subjects affected / exposed
    8 / 47 (17.02%)
    9 / 49 (18.37%)
         occurrences all number
    17
    16
    Abdominal distension
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    11 / 47 (23.40%)
    4 / 49 (8.16%)
         occurrences all number
    14
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 49 (2.04%)
         occurrences all number
    3
    1
    Rash
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 49 (6.12%)
         occurrences all number
    2
    4
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 49 (4.08%)
         occurrences all number
    9
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 49 (4.08%)
         occurrences all number
    5
    2
    Arthralgia
         subjects affected / exposed
    2 / 47 (4.26%)
    7 / 49 (14.29%)
         occurrences all number
    2
    7
    Muscle spasms
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 49 (8.16%)
         occurrences all number
    4
    4
    Myalgia
         subjects affected / exposed
    5 / 47 (10.64%)
    5 / 49 (10.20%)
         occurrences all number
    5
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 49 (8.16%)
         occurrences all number
    5
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 49 (6.12%)
         occurrences all number
    4
    6
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    7 / 49 (14.29%)
         occurrences all number
    1
    7
    Influenza
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 49 (6.12%)
         occurrences all number
    1
    3
    Sinusitis
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 49 (6.12%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 49 (0.00%)
         occurrences all number
    3
    0
    Hyponatraemia
         subjects affected / exposed
    6 / 47 (12.77%)
    1 / 49 (2.04%)
         occurrences all number
    15
    1
    Hyperglycaemia
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    Hypokalaemia
         subjects affected / exposed
    14 / 47 (29.79%)
    2 / 49 (4.08%)
         occurrences all number
    40
    2
    Hypertriglyceridaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 49 (2.04%)
         occurrences all number
    5
    1
    Decreased appetite
         subjects affected / exposed
    5 / 47 (10.64%)
    8 / 49 (16.33%)
         occurrences all number
    5
    10
    Hypocalcaemia
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 49 (0.00%)
         occurrences all number
    9
    0
    Hypophosphataemia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 49 (0.00%)
         occurrences all number
    4
    0
    Hypoalbuminaemia
         subjects affected / exposed
    7 / 47 (14.89%)
    1 / 49 (2.04%)
         occurrences all number
    15
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Mar 2021
    1. Updated to clarify that the independent Data Monitoring Committee reviewed safety data and efficacy data. 2. Inclusion and exclusion criteria were updated. 3. Updated the number of times that the NCI PRO-CTCAE patient-reported outcome questionnaire will be administered during cycles 1, 2, and 3 [from twice (Days 1 and 15) to three times (Days 1, 8, and 15)]. 4. The Schedule of Assessments has been updated to introduce additional visits for safety assessments on Day 10 (±3 days) of Cycle 1 and Cycle 2.
    22 Feb 2022
    1. Increased the window for prescreening testing from 6 months to 12 months, and revised that up to two prescreening samples can be sent for analysis 2. Updated to provide guidance for HER2 and PD-L1 assessment in participants with initially multicentric tumors (multiple tumors involving more than one quadrant) or multifocal tumors (more than one mass confined to the same quadrant as the primary tumor). 3. Clarified that the use of hormonal contraceptives and hormone releasing intrauterine devices are prohibited in women with hormone receptor-positive tumors. 4. Updated to add a time window (+/- 10 minutes) for the infusions of trastuzumab emtansine, and guidance on the premedications that can be used for the second and subsequent infusions of trastuzumab emtansine have been added
    02 Mar 2023
    1. Revisions have been made to the study objectives to indicate which objectives are no longer applicable and the corresponding analyses that were no longer be performed. 2. The end of study and length of study have been updated. 3. The planned analyses for both PFS and OS in the context of the premature study termination have been clarified, as well as the impact of the premature study termination on the study sample size.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Jun 2024
    The Sponsor decided to prematurely terminate the study due to a lower-than-expected enrollment rate.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The Sponsor decided to prematurely terminate the study due to a lower-than-expected enrollment rate.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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