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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label Phase III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine Versus Trastuzumab As Adjuvant Therapy For Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically In The Breast Or Axillary Lymph Nodes Following Preoperative Therapy.

    Summary
    EudraCT number
    2012-002018-37
    Trial protocol
    BE   SE   AT   CZ   DE   GB   IT   IE   ES   GR   FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Aug 2019
    First version publication date
    23 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BO27938
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01772472
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +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
    25 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2018
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.
    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
    03 Apr 2013
    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
    Canada: 58
    Country: Number of subjects enrolled
    United States: 276
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Brazil: 45
    Country: Number of subjects enrolled
    China: 26
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    Guatemala: 22
    Country: Number of subjects enrolled
    Hong Kong: 15
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Mexico: 25
    Country: Number of subjects enrolled
    Panama: 13
    Country: Number of subjects enrolled
    Peru: 8
    Country: Number of subjects enrolled
    Serbia: 23
    Country: Number of subjects enrolled
    South Africa: 20
    Country: Number of subjects enrolled
    Taiwan: 60
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    France: 139
    Country: Number of subjects enrolled
    Germany: 291
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Ireland: 34
    Country: Number of subjects enrolled
    Italy: 110
    Country: Number of subjects enrolled
    Spain: 92
    Country: Number of subjects enrolled
    Sweden: 25
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    United Kingdom: 71
    Worldwide total number of subjects
    1486
    EEA total number of subjects
    819
    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)
    1360
    From 65 to 84 years
    126
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    1486 patients were randomized in 268 centers across 28 countries.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trastuzumab
    Arm description
    Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    6 mg/kg intravenously every 3 weeks, 14 cycles

    Arm title
    Trastuzumab emtansine
    Arm description
    Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.
    Arm type
    Experimental

    Investigational medicinal product name
    trastuzumab emtansine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3.6 mg/kg intravenously every 3 weeks, 14 cycles

    Number of subjects in period 1
    Trastuzumab Trastuzumab emtansine
    Started
    743
    743
    Completed
    0
    0
    Not completed
    743
    743
         Death
    56
    42
         Physician decision
    1
    3
         Ongoing
    597
    635
         Consent withdrawn by subject
    72
    50
         Lost to follow-up
    12
    8
         Not Specified
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.

    Reporting group title
    Trastuzumab emtansine
    Reporting group description
    Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.

    Reporting group values
    Trastuzumab Trastuzumab emtansine Total
    Number of subjects
    743 743 1486
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0
        Between 18 and 65 years
    675 685 1360
        >=65 years
    68 58 126
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.2 ± 10.9 49.0 ± 10.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    740 741 1481
        Male
    3 2 5
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    50 36 86
        Asian
    64 65 129
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    19 21 40
        White
    531 551 1082
        More than one race
    1 1 2
        Unknown or Not Reported
    77 69 146

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.

    Reporting group title
    Trastuzumab emtansine
    Reporting group description
    Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.

    Primary: Invasive disease-free survival (IDFS)

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    End point title
    Invasive disease-free survival (IDFS)
    End point description
    IDFS event was defined as the first occurrence of one of the following events: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site - other than the two above mentioned sites); death attributable to any cause; contralateral invasive breast cancer. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
    End point type
    Primary
    End point timeframe
    From randomization up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Probability
        number (confidence interval 95%)
    77.02 (73.78 to 80.26)
    88.27 (85.81 to 90.72)
    Statistical analysis title
    IDFS
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Trastuzumab v Trastuzumab emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    0.64

    Secondary: Invasive disease-free survival including second primary non-breast cancer

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    End point title
    Invasive disease-free survival including second primary non-breast cancer
    End point description
    IDFS including second primary non-breast cancer was defined the same way as IDFS for the primary endpoint but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ (CIS) of any site). 3-year IDFS including second primary non-breast cancer event-free rates per treatment arm in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
    End point type
    Secondary
    End point timeframe
    From baseline up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Probability
        number (confidence interval 95%)
    76.89 (73.65 to 80.14)
    87.68 (85.18 to 90.18)
    Statistical analysis title
    IDFS Including Second Primary Non-Breast Cancer
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Trastuzumab v Trastuzumab emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.66

    Secondary: Disease-free survival

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    End point title
    Disease-free survival
    End point description
    Disease-free survival was defined as the time between randomization and the date of the first occurrence of an invasive disease-free survival event including second primary non-breast cancer event or contralateral or ipsilateral DCIS. 3-year DFS event-free rates per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
    End point type
    Secondary
    End point timeframe
    From baseline up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Probability
        number (confidence interval 95%)
    76.89 (73.65 to 80.14)
    87.41 (84.88 to 89.93)
    Statistical analysis title
    DFS
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Trastuzumab v Trastuzumab emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.41
         upper limit
    0.68

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. 5 years OS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 5 years after randomization.
    End point type
    Secondary
    End point timeframe
    Baseline up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Probability
        number (confidence interval 95%)
    86.79 (80.95 to 92.63)
    92.09 (89.44 to 94.74)
    Statistical analysis title
    OS
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Trastuzumab v Trastuzumab emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0848
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.47
         upper limit
    1.05

    Secondary: Distant Recurrence-Free Interval (DRFI)

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    End point title
    Distant Recurrence-Free Interval (DRFI)
    End point description
    DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3 years DRFI event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
    End point type
    Secondary
    End point timeframe
    Baseline up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Probability
        number (confidence interval 95%)
    83.01 (80.10 to 85.92)
    89.69 (87.37 to 92.01)
    Statistical analysis title
    DRFI
    Statistical analysis description
    Unstratified analysis
    Comparison groups
    Trastuzumab v Trastuzumab emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.45
         upper limit
    0.79

    Secondary: Percentage of Participants with Adverse Events

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    End point title
    Percentage of Participants with Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a 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. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).
    End point type
    Secondary
    End point timeframe
    From Day 1 to 30 days after last dose of study drug, up to the clinical cutoff date (approximately 64 months)
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    720
    740
    Units: Percentage of Participants
        number (not applicable)
    93.3
    98.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Cardiac Dysfunction

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    End point title
    Percentage of Participants with Cardiac Dysfunction
    End point description
    Cardiac events were reported based on the NCI-CTCAE, v4.0.
    End point type
    Secondary
    End point timeframe
    From baseline up to 10 years
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    720
    740
    Units: Percentage of Participants
        number (not applicable)
    5.6
    3.1
    No statistical analyses for this end point

    Secondary: Change from Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)

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    End point title
    Change from Baseline of Functional Scales, Symptom Scales and Single Items in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)
    End point description
    The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive value means an increase, while a negative value means a decrease, in score at the indicated time-point relative to the score at baseline (Cycle 1, Day 1).
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 5, 11, Follow-up (FU) Month 6, Follow-up Month 12
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline: Appetite Loss
    7.9 ± 17.4
    7.1 ± 16.4
        Change at Cycle 5: Appetite Loss
    1.0 ± 18.7
    6.5 ± 23.7
        Change at Cycle 11: Appetite Loss
    -0.5 ± 17.2
    2.9 ± 20.2
        Change at FU Month 6: Appetite Loss
    -1.6 ± 18.3
    -1.7 ± 19.9
        Change at FU Month 12: Appetite Loss
    0.5 ± 20.3
    -1.9 ± 20.1
        Baseline: Constipation
    9.8 ± 20.2
    9.5 ± 19.0
        Change at Cycle 5: Constipation
    1.0 ± 22.4
    4.6 ± 22.6
        Change at Cycle 11: Constipation
    3.4 ± 23.6
    7.3 ± 23.1
        Change at FU Month 6: Constipation
    4.1 ± 23.7
    3.7 ± 23.3
        Change at FU Month 12: Constipation
    3.2 ± 23.2
    4.3 ± 24.6
        Baseline: Diarrhea
    8.8 ± 17.6
    6.4 ± 14.9
        Change at Cycle 5: Diarrhea
    -1.6 ± 19.3
    -1.5 ± 19.5
        Change at Cycle 11: Diarrhea
    -0.4 ± 21.4
    -2.4 ± 17.5
        Change at FU Month 6: Diarrhea
    -3.4 ± 18.5
    -1.9 ± 18.3
        Change at FU Month 12: Diarrhea
    -2.8 ± 18.9
    -1.6 ± 18.4
        Baseline: Dyspnea
    12.7 ± 20.7
    11.0 ± 18.8
        Change at Cycle 5: Dyspnea
    2.3 ± 21.9
    4.1 ± 22.4
        Change at Cycle 11: Dyspnea
    2.8 ± 21.2
    2.7 ± 20.4
        Change at FU Month 6: Dyspnea
    3.3 ± 22.8
    3.8 ± 22.7
        Change at FU Month 12: Dyspnea
    3.9 ± 24.9
    5.3 ± 22.4
        Baseline: Fatigue
    29.2 ± 21.1
    28.0 ± 20.0
        Change at Cycle 5: Fatigue
    1.1 ± 20.1
    5.5 ± 19.7
        Change at Cycle 11: Fatigue
    1.1 ± 20.5
    3.8 ± 21.3
        Change at FU Month 6: Fatigue
    -1.4 ± 21.9
    -0.1 ± 22.2
        Change at FU Month 12: Fatigue
    -0.1 ± 23.3
    -0.1 ± 22.1
        Baseline: Financial Difficulties
    28.6 ± 33.3
    27.6 ± 31.9
        Change at Cycle 5: Financial Difficulties
    -3.1 ± 26.5
    -3.0 ± 28.0
        Change at Cycle 11: Financial Difficulties
    -5.1 ± 27.6
    -1.7 ± 28.7
        Change at FU Month 6: Financial Difficulties
    -8.4 ± 28.3
    -6.5 ± 30.6
        Change at FU Month 12: Financial Difficulties
    -10.9 ± 30.5
    -7.3 ± 31.0
        Baseline: Insomnia
    30.6 ± 30.8
    30.6 ± 29.2
        Change at Cycle 5: Insomnia
    1.9 ± 28.4
    1.3 ± 29.7
        Change at Cycle 11: Insomnia
    2.4 ± 29.9
    1.5 ± 30.3
        Change at FU Month 6: Insomnia
    1.8 ± 31.3
    -0.9 ± 32.1
        Change at FU Month 12: Insomnia
    0.3 ± 30.4
    0.7 ± 31.7
        Baseline: Nausea/Vomiting
    3.3 ± 9.0
    2.8 ± 8.0
        Change at Cycle 5: Nausea/Vomiting
    1.5 ± 11.2
    3.2 ± 12.5
        Change at Cycle 11: Nausea/Vomiting
    1.3 ± 12.8
    3.0 ± 11.8
        Change at FU Month 6: Nausea/Vomiting
    0.8 ± 10.4
    0.2 ± 11.1
        Change at FU Month 12: Nausea/Vomiting
    0.4 ± 10.5
    1.2 ± 10.9
        Baseline: Pain
    22.2 ± 22.2
    22.6 ± 22.8
        Change at Cycle 5: Pain
    0.0 ± 23.2
    1.8 ± 23.9
        Change at Cycle 11: Pain
    0.1 ± 23.1
    2.1 ± 24.4
        Change at FU Month 6: Pain
    -0.3 ± 24.6
    -0.5 ± 24.3
        Change at FU Month 12: Pain
    -1.2 ± 25.6
    -0.8 ± 25.4
        Baseline: Cognitive Functioning
    83.3 ± 20.2
    84.4 ± 19.0
        Change at Cycle 5: Cognitive Functioning
    -3.8 ± 18.4
    -4.5 ± 18.7
        Change at Cycle 11: Cognitive Functioning
    -5.4 ± 21.3
    -5.3 ± 19.6
        Change at FU Month 6: Cognitive Functioning
    -4.1 ± 22.0
    -6.1 ± 21.6
        Change at FU Month 12: Cognitive Functioning
    -4.9 ± 22.2
    -6.9 ± 21.7
        Baseline: Emotional Functioning
    75.0 ± 22.0
    75.2 ± 21.2
        Change at Cycle 5: Emotional Functioning
    -0.4 ± 20.0
    -1.3 ± 21.3
        Change at Cycle 11: Emotional Functioning
    -1.0 ± 21.3
    0.1 ± 22.0
        Change at FU Month 6: Emotional Functioning
    -2.9 ± 22.0
    -0.8 ± 23.3
        Change at FU Month 12: Emotional Functioning
    -2.0 ± 22.7
    -1.6 ± 23.5
        Baseline: Physical Functioning
    84.5 ± 15.3
    85.8 ± 14.1
        Change at Cycle 5: Physical Functioning
    0.3 ± 12.9
    -1.6 ± 12.7
        Change at Cycle 11: Physical Functioning
    1.9 ± 14.2
    -0.6 ± 14.6
        Change at FU Month 6: Physical Functioning
    2.8 ± 15.4
    0.7 ± 15.1
        Change at FU Month 12: Physical Functioning
    2.7 ± 14.5
    0.8 ± 14.5
        Baseline: Role Functioning
    77.5 ± 25.0
    78.6 ± 23.3
        Change at Cycle 5: Role Functioning
    2.0 ± 24.3
    -0.2 ± 24.1
        Change at Cycle 11: Role Functioning
    4.0 ± 24.3
    0.6 ± 24.5
        Change at FU Month 6: Role Functioning
    7.4 ± 25.8
    3.6 ± 26.7
        Change at FU Month 12: Role Functioning
    8.0 ± 27.5
    4.6 ± 25.5
        Baseline: Social Functioning
    77.1 ± 24.1
    76.8 ± 23.2
        Change at Cycle 5: Social Functioning
    4.0 ± 22.5
    1.6 ± 23.8
        Change at Cycle 11: Social Functioning
    5.8 ± 24.0
    2.5 ± 23.6
        Change at FU Month 6: Social Functioning
    8.5 ± 23.7
    6.5 ± 26.1
        Change at FU Month 12: Social Functioning
    9.5 ± 25.1
    7.4 ± 26.4
        Baseline: Global Health Status
    71.2 ± 19.3
    71.4 ± 18.0
        Change at Cycle 5: Global Health Status
    0.6 ± 18.9
    -1.9 ± 19.6
        Change at Cycle 11: Global Health Status
    1.7 ± 17.8
    -0.5 ± 19.9
        Change at FU Month 6: Global Health Status
    2.5 ± 19.3
    2.0 ± 19.2
        Change at FU Month 12: Global Health Status
    3.2 ± 19.5
    2.8 ± 20.1
    No statistical analyses for this end point

    Secondary: Change from Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)

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    End point title
    Change from Baseline of Four Functioning Scales and Four Symptom Scales in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)
    End point description
    EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective [FP]) and four symptom scales (systemic side effects [SE], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores averaged and transformed to 0-100 scale. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated improvement in quality of life (QOL) and negative change from baseline indicated a deterioration in QOL. For symptom scales, positive change from baseline indicated a deterioration in quality of life (QOL) and negative change from baseline indicated an improvement in QOL.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 5, 11, Follow-up Month 6, Follow-up Month 12
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    743
    743
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Baseline: Body Image
    69.8 ± 28.5
    67.5 ± 28.5
        Change at Cycle 5: Body Image
    1.5 ± 20.5
    4.6 ± 22.7
        Change at Cycle 11: Body Image
    3.4 ± 24.4
    5.7 ± 23.9
        Change at FU Month 6: Body Image
    3.6 ± 25.1
    7.8 ± 25.8
        Change at FU Month 12: Body Image
    6.2 ± 27.1
    6.1 ± 27.2
        Baseline: FP
    51.3 ± 31.2
    50.1 ± 31.7
        Change at Cycle 5: FP
    2.6 ± 28.3
    6.5 ± 29.9
        Change at Cycle 11: FP
    6.3 ± 30.0
    6.1 ± 31.4
        Change at FU Month 6: FP
    7.7 ± 33.5
    8.1 ± 34.6
        Change at FU Month 12: FP
    8.1 ± 31.1
    8.2 ± 33.0
        Baseline: Sexual Enjoyment
    50.9 ± 28.8
    52.3 ± 28.5
        Change at Cycle 5: Sexual Enjoyment
    2.3 ± 26.4
    -1.9 ± 24.6
        Change at Cycle 11: Sexual Enjoyment
    4.4 ± 27.5
    4.4 ± 24.5
        Change at FU Month 6: Sexual Enjoyment
    3.2 ± 28.1
    0.3 ± 27.5
        Change at FU Month 12: Sexual Enjoyment
    5.6 ± 26.0
    1.8 ± 26.2
        Baseline: Sexual Function
    20.2 ± 23.6
    22.0 ± 23.4
        Change at Cycle 5: Sexual Function
    3.3 ± 20.0
    2.3 ± 20.0
        Change at Cycle 11: Sexual Function
    3.1 ± 20.8
    1.9 ± 20.3
        Change at FU Month 6: Sexual Function
    5.1 ± 23.9
    4.3 ± 23.1
        Change at FU Month 12: Sexual Function
    5.9 ± 23.7
    5.2 ± 22.7
        Baseline: Arm Symptoms
    24.6 ± 21.1
    24.5 ± 21.0
        Change at Cycle 5: Arm Symptoms
    -2.8 ± 20.9
    -2.6 ± 23.0
        Change at Cycle 11: Arm Symptoms
    -2.6 ± 21.2
    0.2 ± 24.2
        Change at FU Month 6: Arm Symptoms
    -3.0 ± 23.5
    -1.3 ± 24.2
        Change at FU Month 12: Arm Symptoms
    -5.7 ± 22.8
    -1.5 ± 22.6
        Baseline: Breast Symptoms
    22.7 ± 19.1
    21.4 ± 17.9
        Change at Cycle 5: Breast Symptoms
    -1.1 ± 20.3
    -1.1 ± 19.1
        Change at Cycle 11: Breast Symptoms
    -3.7 ± 19.8
    -0.6 ± 19.5
        Change at FU Month 6: Breast Function
    -6.5 ± 20.0
    -2.2 ± 19.7
        Change at Follow-up Month 12: Breast Function
    -8.3 ± 19.9
    -3.8 ± 19.2
        Baseline: Systemic Therapy Side Effects (SE)
    16.7 ± 13.7
    16.9 ± 14.1
        Change at Cycle 5: Systemic Therapy SE
    0.7 ± 13.0
    5.5 ± 15.3
        Change at Cycle 11: Systemic Therapy SE
    1.2 ± 12.2
    4.2 ± 15.4
        Change at FU Month 6: Systemic Therapy SE
    1.9 ± 13.9
    1.1 ± 15.3
        Change at FU Month 12: Systemic Therapy SE
    1.3 ± 13.9
    1.4 ± 16.3
        Baseline: Upset by Hair Loss Item
    40.3 ± 35.6
    50.7 ± 38.4
        Change at Cycle 5: Upset by Hair Loss Item
    -5.1 ± 38.1
    -17.6 ± 39.3
        Change at Cycle 11: Upset by Hair Loss Item
    -28.6 ± 45.0
    -14.3 ± 33.9
        Change at FU Month 6: Upset by Hair Loss Item
    -12.0 ± 47.0
    -15.2 ± 42.1
        Change at FU Month 12: Upset by Hair Loss Item
    -2.9 ± 37.5
    -14.3 ± 41.6
    No statistical analyses for this end point

    Secondary: Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (including Total Trastuzumab and DM1)

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    End point title
    Serum Concentrations (Area Under the Concentration-time Curve [AUC]) of Trastuzumab Emtansine (including Total Trastuzumab and DM1)
    End point description
    Blood and serum samples for measurement of trastuzumab emtansine, total trastuzumab, and DM1 will be obtained from patients randomized to the trastuzumab emtansine arm.
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1, Day (D) 1 and C4D1 of pre-infusion, C1D1 and C4D1 post-infusion, C2D1 and C5D1 pre-infusion and study treatment termination
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [1] - As the data is not mature yet, this endpoint will be presented at final analysis stage.
    [2] - As the data is not mature yet, this endpoint will be presented at final analysis stage.
    No statistical analyses for this end point

    Secondary: Serum Concentrations (AUC) of Trastuzumab

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    End point title
    Serum Concentrations (AUC) of Trastuzumab
    End point description
    Serum blood samples were collected for trastuzumab measurement prior to dosing and 15-30 minutes post infusion for Cycle 1 and Cycle 4. Additional serum samples were collected at study treatment termination.
    End point type
    Secondary
    End point timeframe
    C1D1 and C4D1 of post-infusion and study treatment termination
    End point values
    Trastuzumab Trastuzumab emtansine
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: ug/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [3] - As the data is not mature yet, this endpoint will be presented at final analysis stage.
    [4] - As the data is not mature yet, this endpoint will be presented at final analysis stage.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to primary clinical cutoff date of approximately 64 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Trastuzumab emtansine
    Reporting group description
    Participants received trastuzumab emtansine 3.6 mg/kg IV every 3 weeks for 14 cycles.

    Reporting group title
    Trastuzumab
    Reporting group description
    Participants received trastuzumab 6 milligrams/kilogram (mg/kg) intravenously (IV) every 3 weeks for 14 cycles.

    Serious adverse events
    Trastuzumab emtansine Trastuzumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    94 / 740 (12.70%)
    58 / 720 (8.06%)
         number of deaths (all causes)
    42
    56
         number of deaths resulting from adverse events
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 740 (0.14%)
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer Stage 1
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial Adenocarcinoma
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary Tumour Benign
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    4 / 740 (0.54%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest pain
         subjects affected / exposed
    3 / 740 (0.41%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza Like Illness
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Haemorrhage
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Obstruction
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine Prolapse
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Wound Dehiscence
         subjects affected / exposed
    3 / 740 (0.41%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural haemorrhage
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation Pneumonitis
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia Fracture
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle Fracture
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb Fracture
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Complication
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet Count Decreased
         subjects affected / exposed
    10 / 740 (1.35%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    9 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection Fraction Decreased
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin T Increased
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (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
         subjects affected / exposed
    2 / 740 (0.27%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (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 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (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
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    3 / 740 (0.41%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Motor Neuropathy
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 740 (0.41%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    3 / 740 (0.41%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileal Perforation
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric Emptying
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large Intestinal Obstruction
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Pain
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular Regenerative Hyperplasia
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder Polyp
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Cyst
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Telangiectasia
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Mastitis
         subjects affected / exposed
    8 / 740 (1.08%)
    6 / 720 (0.83%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    6 / 740 (0.81%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 740 (0.41%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 740 (0.41%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    2 / 740 (0.27%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    2 / 740 (0.27%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 740 (0.14%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 740 (0.14%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 740 (0.14%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 740 (0.27%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess Intestinal
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis Infections
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant Site Cellulitis
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected Seroma
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal Abscess
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 740 (0.00%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvitis
         subjects affected / exposed
    1 / 740 (0.14%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Trastuzumab emtansine Trastuzumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    719 / 740 (97.16%)
    634 / 720 (88.06%)
    Vascular disorders
    Hot Flush
         subjects affected / exposed
    95 / 740 (12.84%)
    146 / 720 (20.28%)
         occurrences all number
    99
    154
    Lymphoedema
         subjects affected / exposed
    37 / 740 (5.00%)
    48 / 720 (6.67%)
         occurrences all number
    37
    51
    Hypertension
         subjects affected / exposed
    41 / 740 (5.54%)
    34 / 720 (4.72%)
         occurrences all number
    58
    38
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    366 / 740 (49.46%)
    243 / 720 (33.75%)
         occurrences all number
    456
    276
    Influenza like Illness
         subjects affected / exposed
    100 / 740 (13.51%)
    86 / 720 (11.94%)
         occurrences all number
    138
    96
    Pain
         subjects affected / exposed
    93 / 740 (12.57%)
    92 / 720 (12.78%)
         occurrences all number
    114
    113
    Oedema Peripheral
         subjects affected / exposed
    29 / 740 (3.92%)
    52 / 720 (7.22%)
         occurrences all number
    33
    56
    Pyrexia
         subjects affected / exposed
    76 / 740 (10.27%)
    29 / 720 (4.03%)
         occurrences all number
    98
    32
    Chills
         subjects affected / exposed
    39 / 740 (5.27%)
    14 / 720 (1.94%)
         occurrences all number
    57
    16
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    101 / 740 (13.65%)
    86 / 720 (11.94%)
         occurrences all number
    110
    95
    Depression
         subjects affected / exposed
    41 / 740 (5.54%)
    44 / 720 (6.11%)
         occurrences all number
    44
    47
    Anxiety
         subjects affected / exposed
    27 / 740 (3.65%)
    42 / 720 (5.83%)
         occurrences all number
    29
    44
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    53 / 740 (7.16%)
    42 / 720 (5.83%)
         occurrences all number
    56
    50
    Injury, poisoning and procedural complications
    Radiation Skin Injury
         subjects affected / exposed
    188 / 740 (25.41%)
    199 / 720 (27.64%)
         occurrences all number
    198
    208
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    171 / 740 (23.11%)
    41 / 720 (5.69%)
         occurrences all number
    208
    51
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    209 / 740 (28.24%)
    40 / 720 (5.56%)
         occurrences all number
    253
    44
    Platelet Count Decreased
         subjects affected / exposed
    205 / 740 (27.70%)
    17 / 720 (2.36%)
         occurrences all number
    256
    21
    Neutrophil Count Decreased
         subjects affected / exposed
    61 / 740 (8.24%)
    36 / 720 (5.00%)
         occurrences all number
    78
    46
    White Blood Cell Count Decreased
         subjects affected / exposed
    61 / 740 (8.24%)
    42 / 720 (5.83%)
         occurrences all number
    81
    62
    Blood Bilirubin Increased
         subjects affected / exposed
    49 / 740 (6.62%)
    2 / 720 (0.28%)
         occurrences all number
    74
    2
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    61 / 740 (8.24%)
    13 / 720 (1.81%)
         occurrences all number
    68
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    100 / 740 (13.51%)
    86 / 720 (11.94%)
         occurrences all number
    112
    93
    Epistaxis
         subjects affected / exposed
    158 / 740 (21.35%)
    25 / 720 (3.47%)
         occurrences all number
    220
    30
    Dyspnoea
         subjects affected / exposed
    62 / 740 (8.38%)
    52 / 720 (7.22%)
         occurrences all number
    69
    56
    Oropharyngeal Pain
         subjects affected / exposed
    37 / 740 (5.00%)
    33 / 720 (4.58%)
         occurrences all number
    39
    36
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    74 / 740 (10.00%)
    60 / 720 (8.33%)
         occurrences all number
    89
    79
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    69 / 740 (9.32%)
    57 / 720 (7.92%)
         occurrences all number
    76
    61
    Headache
         subjects affected / exposed
    210 / 740 (28.38%)
    122 / 720 (16.94%)
         occurrences all number
    287
    146
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    135 / 740 (18.24%)
    50 / 720 (6.94%)
         occurrences all number
    146
    51
    Paraesthesia
         subjects affected / exposed
    60 / 740 (8.11%)
    40 / 720 (5.56%)
         occurrences all number
    72
    43
    Dysgeusia
         subjects affected / exposed
    60 / 740 (8.11%)
    11 / 720 (1.53%)
         occurrences all number
    61
    12
    Eye disorders
    Lacrimation Increased
         subjects affected / exposed
    41 / 740 (5.54%)
    13 / 720 (1.81%)
         occurrences all number
    44
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    308 / 740 (41.62%)
    93 / 720 (12.92%)
         occurrences all number
    438
    111
    Diarrhoea
         subjects affected / exposed
    91 / 740 (12.30%)
    89 / 720 (12.36%)
         occurrences all number
    117
    116
    Vomiting
         subjects affected / exposed
    106 / 740 (14.32%)
    37 / 720 (5.14%)
         occurrences all number
    139
    45
    Constipation
         subjects affected / exposed
    126 / 740 (17.03%)
    59 / 720 (8.19%)
         occurrences all number
    152
    66
    Dry Mouth
         subjects affected / exposed
    100 / 740 (13.51%)
    9 / 720 (1.25%)
         occurrences all number
    109
    9
    Stomatitis
         subjects affected / exposed
    80 / 740 (10.81%)
    27 / 720 (3.75%)
         occurrences all number
    96
    29
    Abdominal Pain
         subjects affected / exposed
    55 / 740 (7.43%)
    42 / 720 (5.83%)
         occurrences all number
    66
    48
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    51 / 740 (6.89%)
    42 / 720 (5.83%)
         occurrences all number
    57
    44
    Dry Skin
         subjects affected / exposed
    48 / 740 (6.49%)
    36 / 720 (5.00%)
         occurrences all number
    52
    41
    Dermatitis Acneiform
         subjects affected / exposed
    39 / 740 (5.27%)
    21 / 720 (2.92%)
         occurrences all number
    44
    23
    Rash Maculo-Papular
         subjects affected / exposed
    42 / 740 (5.68%)
    26 / 720 (3.61%)
         occurrences all number
    49
    27
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    114 / 740 (15.41%)
    80 / 720 (11.11%)
         occurrences all number
    125
    87
    Arthralgia
         subjects affected / exposed
    192 / 740 (25.95%)
    148 / 720 (20.56%)
         occurrences all number
    221
    162
    Pain In Extremity
         subjects affected / exposed
    86 / 740 (11.62%)
    70 / 720 (9.72%)
         occurrences all number
    97
    81
    Back Pain
         subjects affected / exposed
    53 / 740 (7.16%)
    66 / 720 (9.17%)
         occurrences all number
    56
    73
    Muscle Spasms
         subjects affected / exposed
    33 / 740 (4.46%)
    45 / 720 (6.25%)
         occurrences all number
    36
    45
    Bone Pain
         subjects affected / exposed
    52 / 740 (7.03%)
    35 / 720 (4.86%)
         occurrences all number
    55
    38
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    62 / 740 (8.38%)
    16 / 720 (2.22%)
         occurrences all number
    70
    19
    Hypokalaemia
         subjects affected / exposed
    48 / 740 (6.49%)
    14 / 720 (1.94%)
         occurrences all number
    58
    20
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    58 / 740 (7.84%)
    53 / 720 (7.36%)
         occurrences all number
    69
    65
    Urinary Tract Infection
         subjects affected / exposed
    64 / 740 (8.65%)
    37 / 720 (5.14%)
         occurrences all number
    79
    39

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2013
    Clarification and details of IHC and ISH assays used for determining HER2 status were made. Inclusion of patients who had received dose-dense chemotherapy regimens, provided at least 8 weeks of taxane-based therapy and at least 8 weeks of trastuzumab had been given. Revision of language to differentiate radiotherapy for T3 disease with and without lymph node involvement. Recommendations for hormonal therapy were revised to allow 5 to 10 years, rather than only 5 years, of tamoxifen therapy as a result of changing practice guidelines. Guidelines for managing the specific adverse events of nodular regenerative hyperplasia and interstitial lung disease were added. For nodular regenerative hyperplasia, a new appendix for guidelines for liver biopsy was added. Radiotherapy-related toxicity was split into interstitial lung disease and skin toxicity, in order to differentiate between radiation-induced and drug-induced toxicities. Text on use of strong/potent CYP3A4/5 inhibitors was revised to provide further instruction to investigators, and remove erythromycin from the list of examples as it is only a moderate CYP3A4/5 inhibitor, not a potent inhibitor. Suspected transmission of an infection agent by the study drug was added as an adverse event of special interest.
    06 Sep 2013
    The duration of patient monitoring following first dose of trastuzumab emtansine was changed from 60 minutes to 90 minutes. Assessment of total protein at baseline was added to the list of assessments because it was inadvertently omitted. Requirements for long-term reporting of concomitant medication, adverse events and serious adverse events were clarified. Detail on severe/fatal hemorrhage was added under the identified risk of hematologic toxicity.
    28 Mar 2014
    Addition of language to allow shorter duration of an escalated dose-dense administration of paclitaxel. Inclusion criteria were revised to clarify that if pre-chemotherapy LVEF assessments were not conducted, the screening LVEF assessment must be at least 55% in order for the patient to be eligible. Dose modifications related to increases in AST and for thrombocytopenia were revised. Guidelines for Grade 1-2 pneumonitis were updated such that to require diagnosis of drug-related ILD/pneumonitis should lead to permanent discontinuation of trastuzumab emtansine treatment.
    13 Oct 2015
    The reporting of LVSD events as SAEs was clarified. Pregnancy reporting requirements were updated, in line with the Global Enhancement Pharmacovigilance Pregnancy Program.
    09 Jul 2019
    Updated to correct a small but significant error in language in the general inclusion critieria, and indicate that left ventricular ejection fraction (LVEF) should be ≥50% prior to receiving neoadjuvant chemotherapy instead of after receiving neoadjuvant chemotherapy.

    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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