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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination with Atezolizumab or Atezolizumab-Placebo in Patients with HER2-Positive Locally Advanced or Metastatic Breast Cancer who Have Received Prior Trastuzumab and Taxane Based Therapy

    Summary
    EudraCT number
    		 2015-004189-27
    Trial protocol
    		 DE   ES   GB   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    26 Dec 2018
    First version publication date
    26 Dec 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    WO30085
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02924883
    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
    11 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Dec 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This Phase II, double-blind, randomized, placebo-controlled multicenter study investigated the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with HER2-positive locally advanced or metastatic BC who have received prior trastuzumab and taxane based therapy, either alone or in combination, and/or who have progressed within 6 months after completing adjuvant therapy.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Sep 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    United Kingdom: 18
    Worldwide total number of subjects
    202
    EEA total number of subjects
    76
    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)
    176
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Approximately 200 patients were enrolled and randomized to both treatment arms in a 1:2 ratio.

    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trastuzumab Emtansine + Placebo
    Arm description
    		 Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 40 months)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    Other name
    Kadcyla
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo (matching to atezolizumab) was administered by IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

    Arm title
    		 Trastuzumab Emtansine + Atezolizumab
    Arm description
    		 Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 40 months)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine was administered 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab 1200 mg was administered by IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor.

    Number of subjects in period 1
    		Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Started
    69
    133
    Completed
    56
    115
    Not completed
    13
    18
         Adverse event, serious fatal
    8
    13
         Consent withdrawn by subject
    5
    4
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 40 months)

    Reporting group title
    Trastuzumab Emtansine + Atezolizumab
    Reporting group description
    		 Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 40 months)

    Reporting group values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab Total
    Number of subjects
    		 69 133 202
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 58 118 176
        From 65-84 years
    		 11 15 26
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.4 ± 10.9 53.7 ± 9.9 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 69 131 200
        Male
    		 0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 23 49 72
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 1 5 6
        White
    		 44 72 116
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 1 5 6
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 10 11
        Not Hispanic or Latino
    		 66 114 180
        Unknown or Not Reported
    		 2 9 11

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 40 months)

    Reporting group title
    Trastuzumab Emtansine + Atezolizumab
    Reporting group description
    		 Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 40 months)

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

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    End point title
    		 Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
    End point description
    PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.
    End point type
    Primary
    End point timeframe
    Baseline up to clinical cut off date (11 Dec 2017)
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    69
    133
    Units: months
        median (confidence interval 95%)
    6.8 (4.0 to 11.1)
    8.2 (5.8 to 10.7)
    Statistical analysis title
    		 Progression-Free Survival
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Atezolizumab
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3332
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.23

    Primary: Percentage of Subjects with Adverse Events

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    End point title
    		 Percentage of Subjects with Adverse Events [1]
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Primary
    End point timeframe
    Baseline up to clinical cut off date (11 Dec 2017)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    68
    132
    Units: percentage of subjects
        number (not applicable)
    95.6
    99.2
    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 was defined as the time from randomization to death from any cause. 9999 = OS event not reached at time of analysis
    End point type
    Secondary
    End point timeframe
    Baseline up to clinical cut off date (11 Dec 2017)
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    69
    133
    Units: Months
        median (confidence interval 95%)
    12.9 (12.8 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Atezolizumab
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4577
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 1.77

    Secondary: Percentage of Subjects With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1

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    End point title
    		 Percentage of Subjects With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1
    End point description
    An OR was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline up to clinical cut off date (11 Dec 2017)
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    69
    133
    Units: Percentage of subjects
        number (not applicable)
    43.5
    45.5
    No statistical analyses for this end point

    Secondary: Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1

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    End point title
    		 Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1
    End point description
    Duration of OR was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first. 9999 = Duration of OR was not reached at time of analysis
    End point type
    Secondary
    End point timeframe
    Baseline up to clinical cut off date (11 Dec 2017)
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    69
    133
    Units: Months
        median (confidence interval 95%)
    9999 (9.9 to 9999)
    9999 (7.1 to 9999)
    Statistical analysis title
    		 Duration of Objective Response
    Comparison groups
    Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Atezolizumab
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6099
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 3.03

    Secondary: Steady State Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine

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    End point title
    		 Steady State Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 hour [h]), 30 minutes (min) after end of infusion (EOI) (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days); at any time during study treatment/early discontinuation visit (approx. 40 months)
    Notes
    [2] - 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: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    75
    Units: ug/mL
        arithmetic mean (standard deviation)
    80.9 ± 21.9
    No statistical analyses for this end point

    Secondary: Steady State Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine

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    End point title
    		 Steady State Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 h) on Day 1 Cycle 1 and 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4 (each cycle = 21 days)
    Notes
    [3] - 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: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    37
    Units: ng/mL
        arithmetic mean (standard deviation)
    5.46 ± 5.42
    No statistical analyses for this end point

    Secondary: Steady State Cmax of Total Trastuzumab

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    End point title
    		 Steady State Cmax of Total Trastuzumab [4]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days)
    Notes
    [4] - 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: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    75
    Units: ug/mL
        arithmetic mean (standard deviation)
    93.1 ± 24.8
    No statistical analyses for this end point

    Secondary: Cycle 4 Cmax of Atezolizumab

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    End point title
    		 Cycle 4 Cmax of Atezolizumab [5]
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 h), 30 min after EOI (over 60 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycles 2, 3, 8, and every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion/early discontinuation (approx. 40 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    67
    Units: ug/mL
        arithmetic mean (standard deviation)
    637 ± 146
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-therapeutic Antibodies (ATAs) to Atezolizumab

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    End point title
    		 Percentage of Participants With Anti-therapeutic Antibodies (ATAs) to Atezolizumab [6]
    End point description
    ATAs are antibodies that inactivate the therapeutic effects of Atezolizumab. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 h) on Day 1 Cycles 1, 2, 3, 4, 8, and every 8 cycles thereafter (each cycle = 21 days) up to 120 days after treatment completion or early discontinuation (approximately 40 months)
    Notes
    [6] - 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: There were no statistical analysis done for this endpoint.
    End point values
    		 Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    124
    Units: Percentage of participants
        number (not applicable)
    12.1
    No statistical analyses for this end point

    Secondary: Percentage of Participants With ATAs to Trastuzumab Emtansine

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    End point title
    		 Percentage of Participants With ATAs to Trastuzumab Emtansine
    End point description
    ATAs are antibodies that inactivate the therapeutic effects of Trastuzumab Emtansine. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).
    End point type
    Secondary
    End point timeframe
    Pre-infusion (0 h) on Day 1 Cycles 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (approximately 40 months)
    End point values
    		 Trastuzumab Emtansine + Placebo Trastuzumab Emtansine + Atezolizumab
    Number of subjects analysed
    61
    116
    Units: Percentage of Participants
        number (not applicable)
    0
    2.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomization to clinical cutoff date of 15 months
    Adverse event reporting additional description
    The safety population is defined as all patients who received at least one dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Trastuzumab Emtansine + Atezolizumab
    Reporting group description
    		 Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 40 months)

    Reporting group title
    Trastuzumab Emtansine + Placebo
    Reporting group description
    		 Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 40 months)

    Serious adverse events
    		 Trastuzumab Emtansine + Atezolizumab Trastuzumab Emtansine + Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 132 (32.58%)
    13 / 68 (19.12%)
         number of deaths (all causes)
    13
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer Pain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (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
    10 / 132 (7.58%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    9 / 12
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    2 / 132 (1.52%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic Attack
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    3 / 132 (2.27%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    3 / 132 (2.27%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower Limb Fracture
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural Haemorrhage
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain Oedema
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy Peripheral
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated Intravascular Coagulation
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histioytosis Haematophagic
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 132 (2.27%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-Abdominal Haemorrhage
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (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 Mass
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of Jaw
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    3 / 132 (2.27%)
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 132 (2.27%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Jaw
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast Cellulitis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 68 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Trastuzumab Emtansine + Atezolizumab Trastuzumab Emtansine + Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 132 (96.21%)
    62 / 68 (91.18%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 132 (2.27%)
    4 / 68 (5.88%)
         occurrences all number
    3
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 132 (17.42%)
    4 / 68 (5.88%)
         occurrences all number
    27
    4
    Chills
         subjects affected / exposed
    19 / 132 (14.39%)
    6 / 68 (8.82%)
         occurrences all number
    24
    8
    Fatigue
         subjects affected / exposed
    49 / 132 (37.12%)
    29 / 68 (42.65%)
         occurrences all number
    70
    41
    Influenza Like Illness
         subjects affected / exposed
    11 / 132 (8.33%)
    8 / 68 (11.76%)
         occurrences all number
    13
    8
    Mucosal Inflammation
         subjects affected / exposed
    12 / 132 (9.09%)
    1 / 68 (1.47%)
         occurrences all number
    16
    1
    Oedema Peripheral
         subjects affected / exposed
    7 / 132 (5.30%)
    3 / 68 (4.41%)
         occurrences all number
    8
    3
    Pyrexia
         subjects affected / exposed
    40 / 132 (30.30%)
    11 / 68 (16.18%)
         occurrences all number
    59
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 132 (14.39%)
    10 / 68 (14.71%)
         occurrences all number
    21
    11
    Dyspnoea
         subjects affected / exposed
    13 / 132 (9.85%)
    7 / 68 (10.29%)
         occurrences all number
    16
    8
    Epistaxis
         subjects affected / exposed
    22 / 132 (16.67%)
    10 / 68 (14.71%)
         occurrences all number
    25
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 132 (1.52%)
    4 / 68 (5.88%)
         occurrences all number
    2
    4
    Insomnia
         subjects affected / exposed
    9 / 132 (6.82%)
    2 / 68 (2.94%)
         occurrences all number
    9
    2
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    20 / 132 (15.15%)
    11 / 68 (16.18%)
         occurrences all number
    24
    13
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    27 / 132 (20.45%)
    11 / 68 (16.18%)
         occurrences all number
    32
    14
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    6 / 132 (4.55%)
    6 / 68 (8.82%)
         occurrences all number
    7
    7
    Weight Decreased
         subjects affected / exposed
    10 / 132 (7.58%)
    3 / 68 (4.41%)
         occurrences all number
    10
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 132 (5.30%)
    2 / 68 (2.94%)
         occurrences all number
    8
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 132 (6.82%)
    8 / 68 (11.76%)
         occurrences all number
    14
    9
    Dysgeusia
         subjects affected / exposed
    7 / 132 (5.30%)
    5 / 68 (7.35%)
         occurrences all number
    8
    6
    Headache
         subjects affected / exposed
    35 / 132 (26.52%)
    17 / 68 (25.00%)
         occurrences all number
    49
    27
    Neuropathy Peripheral
         subjects affected / exposed
    18 / 132 (13.64%)
    6 / 68 (8.82%)
         occurrences all number
    20
    7
    Paraesthesia
         subjects affected / exposed
    7 / 132 (5.30%)
    2 / 68 (2.94%)
         occurrences all number
    14
    2
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    10 / 132 (7.58%)
    3 / 68 (4.41%)
         occurrences all number
    10
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 132 (12.12%)
    2 / 68 (2.94%)
         occurrences all number
    18
    3
    Neutropenia
         subjects affected / exposed
    9 / 132 (6.82%)
    4 / 68 (5.88%)
         occurrences all number
    16
    4
    Thrombocytopenia
         subjects affected / exposed
    35 / 132 (26.52%)
    9 / 68 (13.24%)
         occurrences all number
    75
    16
    Eye disorders
    Dry Eye
         subjects affected / exposed
    8 / 132 (6.06%)
    4 / 68 (5.88%)
         occurrences all number
    8
    4
    Lacrimation Increased
         subjects affected / exposed
    7 / 132 (5.30%)
    1 / 68 (1.47%)
         occurrences all number
    7
    1
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    14 / 132 (10.61%)
    3 / 68 (4.41%)
         occurrences all number
    16
    3
    Constipation
         subjects affected / exposed
    25 / 132 (18.94%)
    10 / 68 (14.71%)
         occurrences all number
    32
    14
    Diarrhoea
         subjects affected / exposed
    31 / 132 (23.48%)
    12 / 68 (17.65%)
         occurrences all number
    43
    13
    Dyspepsia
         subjects affected / exposed
    12 / 132 (9.09%)
    3 / 68 (4.41%)
         occurrences all number
    18
    3
    Nausea
         subjects affected / exposed
    48 / 132 (36.36%)
    27 / 68 (39.71%)
         occurrences all number
    75
    37
    Stomatitis
         subjects affected / exposed
    9 / 132 (6.82%)
    2 / 68 (2.94%)
         occurrences all number
    13
    2
    Vomiting
         subjects affected / exposed
    26 / 132 (19.70%)
    12 / 68 (17.65%)
         occurrences all number
    35
    16
    Abdominal Pain Upper
         subjects affected / exposed
    9 / 132 (6.82%)
    2 / 68 (2.94%)
         occurrences all number
    9
    7
    Dry Mouth
         subjects affected / exposed
    20 / 132 (15.15%)
    8 / 68 (11.76%)
         occurrences all number
    21
    9
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    8 / 132 (6.06%)
    0 / 68 (0.00%)
         occurrences all number
    9
    0
    Pruritus
         subjects affected / exposed
    18 / 132 (13.64%)
    5 / 68 (7.35%)
         occurrences all number
    22
    6
    Rash
         subjects affected / exposed
    27 / 132 (20.45%)
    7 / 68 (10.29%)
         occurrences all number
    34
    11
    Endocrine disorders
    Hypothryroidism
         subjects affected / exposed
    12 / 132 (9.09%)
    2 / 68 (2.94%)
         occurrences all number
    13
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 132 (12.88%)
    6 / 68 (8.82%)
         occurrences all number
    18
    7
    Back Pain
         subjects affected / exposed
    13 / 132 (9.85%)
    6 / 68 (8.82%)
         occurrences all number
    14
    7
    Muscle Spasms
         subjects affected / exposed
    5 / 132 (3.79%)
    6 / 68 (8.82%)
         occurrences all number
    5
    7
    Musculoskeletal Pain
         subjects affected / exposed
    9 / 132 (6.82%)
    2 / 68 (2.94%)
         occurrences all number
    10
    2
    Myalgia
         subjects affected / exposed
    22 / 132 (16.67%)
    9 / 68 (13.24%)
         occurrences all number
    24
    15
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 132 (6.82%)
    1 / 68 (1.47%)
         occurrences all number
    10
    3
    Upper Resipiratory Tract Infection
         subjects affected / exposed
    15 / 132 (11.36%)
    5 / 68 (7.35%)
         occurrences all number
    18
    5
    Urinary Tract Infection
         subjects affected / exposed
    6 / 132 (4.55%)
    6 / 68 (8.82%)
         occurrences all number
    6
    9
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    28 / 132 (21.21%)
    11 / 68 (16.18%)
         occurrences all number
    43
    13
    Hypokalemia
         subjects affected / exposed
    9 / 132 (6.82%)
    4 / 68 (5.88%)
         occurrences all number
    11
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    Study schema related to study drug discontinuation has been clarified with regards to discontinuation for toxicity and treatment beyond progression. Safety, pharmacokinetic, and immunogenicity endpoints for the study have been clarified. Bone scan requirements have been clarified with regards to frequency. On the basis of updated clinical data regarding the atezolizumab half-life of 27 days, the abstinence period and when to use of live vaccine was revised. Tumor specimen requirements have been clarified. Inclusion criteria related to local laboratory assessments for screening have been clarified. Exclusion criteria related to cardiopulmonary dysfunction, patients with severe infection, leptomeningeal disease, washout period of prior anti-cancer therapy has been added/revised. The unblinding of treatment assignment at the patient level for non-safety reasons has been clarified with regards to when this is permitted. The recalculation of the trastuzumab emtansine dose at every cycle based on a patient’s weight has been clarified. The frequency and type of tumor assessments to be performed after the screening period have been specified. On the basis of a review of clinical data, Epstein Barr virus testing is no longer required and has been removed from the protocol. The alpha spending function to be used for testing the primary efficacy endpoint PFS to account for the conduct of one interim analysis was changed from a gamma function with parameter -8 to a gamma function with parameter -1.
    09 Aug 2017
    The interim analysis for PFS has been removed. The number of PFS events for the primary PFS analysis has been increased from 95 to 115. The first analysis of OS will be performed at the time of the primary PFS analysis. Another update for OS will be performed at approximately 12 months after the primary PFS analysis. The final OS analysis will be performed at approximately 24 months after the primary PFS analysis or when ~50% OS events from 200 patients can be obtained, whichever occurs first. The Sponsor may consider additional OS updates beyond 24 months after primary PFS analysis if more mature OS data are requested by the Health Authority. The changes allow for a better understanding of the therapeutic effects of the experimental treatment on OS and provide more mature data for benefit-risk assessment with the additional follow-up period for survival data. The assumed median PFS time for the control arm, trastuzumab emtansine plus placebo, has been changed from 9.6 months (observed in EMILIA study) to 6.2 months (observed in TH3RESA study) to reflect the observed prior treatment demographics of patients enrolled in the study. The estimated time for primary PFS analysis has been changed from approximately 19−21 months after first patient enrolled to approximately 15−17 months after first patient enrolled, due to the updated assumption of median PFS time for the control arm and the updated number of events for primary PFS analysis. The pregnancy reporting process has been clarified and the safety risks for trastuzumab emtansine and atezolizumab have been updated. Brain assessment, brain computed tomography/magnetic resonance imagining requirements, and event reporting for hospitalization have been clarified and the reporting of the term "sudden death" has been updated to also require the presumed cause of death. The process for reviewing and handling protocol deviations has been updated per internal standard operating procedures.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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