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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
    23 May 2024

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Jun 2025
    First version publication date
    23 Aug 2019
    Other versions
    		 v1
    Version creation reason

    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
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study was to evaluate the efficacy of trastuzumab emtansine versus trastuzumab as adjuvant therapy in participants with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who had residual tumors present in the breast or axillary lymph nodes following preoperative therapy. This study also evaluated the safety and pharmacokinetics (PK) of trastuzumab emtansine and trastuzumab.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Apr 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 11 Years
    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
    Czechia: 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
    Türkiye: 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
    748
    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
    		 A total of 1486 participants with HER2-positive primary breast cancer who had residual invasive disease in either the breast or axillary lymph nodes took part in the study at 268 investigative sites across 28 countries from April 03, 2013 to May 23, 2024. Participants were randomized to receive either trastuzumab or trastuzumab emtansine (T-DM1).

    Pre-assignment
    Screening details
    		 1 participant randomized to trastuzumab arm was later re-randomized to T-DM1 arm & received T-DM1. Another participant received 13 cycles of trastuzumab & 1 of T-DM1. Both these participants were included in the trastuzumab ITT & T-DM1 safety analysis. 1 participant in T-DM1 received 9 cycles of trastuzumab & included in trastuzumab safety.

    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 milligram per kilograms (mg/kg), intravenously (IV), every 3 weeks (Q3W), as a maintenance dose for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    HERCEPTIN®
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab, 6 mg/kg, IV was administered Q3W for 14 cycles (1 cycle = 21 days).

    Arm title
    		 Trastuzumab Emtansine
    Arm description
    		 Participants received trastuzumab emtansine, 3.6 mg/kg, IV, Q3W for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    RO5304020
    Other name
    Kadcyla®, Ado-trastuzumab emtansine
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab emtansine, 3.6 mg/kg, IV was administered Q3W for 14 cycles (1 cycle = 21 days).

    Number of subjects in period 1
    		Trastuzumab Trastuzumab Emtansine
    Started
    743
    743
    Safety-evaluable (SE) Population
    720
    740
    Completed
    0
    0
    Not completed
    743
    743
         Physician decision
    1
    7
         Consent withdrawn by subject
    115
    90
         Follow-up Terminated by Sponsor
    441
    495
         Death
    126
    94
         Not Specified
    9
    7
         Lost to follow-up
    51
    50

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    		 Participants received trastuzumab, 6 milligram per kilograms (mg/kg), intravenously (IV), every 3 weeks (Q3W), as a maintenance dose for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first

    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg/kg, IV, Q3W for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first.

    Reporting group values
    		 Trastuzumab Trastuzumab Emtansine Total
    Number of subjects
    		 743 743 1486
    Age Categorical
    Units: participants
        <=18 years
    		 0 0 0
        Between 18 and 65 years
    		 675 685 1360
        >=65 years
    		 68 58 126
    Sex: Female, Male
    Units: participants
        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
    		 530 551 1081
        More than one race
    		 2 1 3
        Unknown or Not Reported
    		 77 69 146
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 107 91 198
        Not Hispanic or Latino
    		 543 579 1122
        Unknown or Not Reported
    		 93 73 166

    End points

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    End points reporting groups
    Reporting group title
    Trastuzumab
    Reporting group description
    		 Participants received trastuzumab, 6 milligram per kilograms (mg/kg), intravenously (IV), every 3 weeks (Q3W), as a maintenance dose for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first

    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 Participants received trastuzumab emtansine, 3.6 mg/kg, IV, Q3W for 14 cycles (1 cycle = 21 days) or until disease recurrence or unacceptable toxicity which ever occurs first.

    Primary: Invasive Disease-free Survival (IDFS) Rate at 3 Years

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    End point title
    		 Invasive Disease-free Survival (IDFS) Rate at 3 Years
    End point description
    IDFS event =the first occurrence of any 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 &/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site-other than the 2 above-mentioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; death attributable to any cause including breast cancer, non-breast cancer or unknown cause . 3-year IDFS rate in ITT population was estimated using Kaplan Meier (KM) method & the percentage of participants who were event-free 3 years after randomization was estimated. ITT population.
    End point type
    Primary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    77.12 (73.96 to 80.28)
    88.44 (86.07 to 90.81)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.66

    Primary: IDFS Rate at 7 Years

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    End point title
    		 IDFS Rate at 7 Years
    End point description
    IDFS=first occurrence of any 1 of following events: ipsilateral invasive breast tumor recurrence (i.e. an invasive breast cancer involving same breast parenchyma as original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e. an invasive breast cancer in axilla, regional lymph nodes, chest wall &/or skin of ipsilateral breast); distant recurrence (i.e. evidence of breast cancer in any anatomic site-other than 2 above-mentioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; death attributable to any cause including breast cancer, non-breast cancer/unknown cause . 7-year IDFS rate in was estimated using Kaplan Meier (KM) method & percentage of participants who were event-free 7 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    67.11 (63.53 to 70.68)
    80.82 (77.86 to 83.78)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.66

    Primary: IDFS Rate at 8 Years

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    End point title
    		 IDFS Rate at 8 Years
    End point description
    IDFS=first occurrence of any 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 2 above-mentioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; death attributable to any cause including breast cancer, non-breast cancer or unknown cause . 8-year IDFS rate in ITT population was estimated using KM method and the percentage of participants who were event-free 8 years after randomization was estimated. ITT population.
    End point type
    Primary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    64.57 (60.90 to 68.23)
    79.11 (76.03 to 82.19)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.66

    Secondary: IDFS Including Second Primary Non-breast Cancer (SPNBC) Rate at 3 Years

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    End point title
    		 IDFS Including Second Primary Non-breast Cancer (SPNBC) Rate at 3 Years
    End point description
    IDFS including SPNBC was defined the same way as IDFS 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). IDFS event was defined as outlined in the description for IDFS rate outcome measure (OM) number 1. 3-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    76.98 (73.82 to 80.15)
    87.87 (85.45 to 90.29)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.69

    Secondary: IDFS Including SPNBC Rate at 8 Years

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    End point title
    		 IDFS Including SPNBC Rate at 8 Years
    End point description
    IDFS including SPNBC was defined the same way as IDFS but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and CIS of any site). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 8-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    63.65 (59.96 to 67.34)
    77.76 (74.60 to 80.92)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.69

    Secondary: IDFS Including SPNBC Rate at 7 Years

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    End point title
    		 IDFS Including SPNBC Rate at 7 Years
    End point description
    IDFS including SPNBC was defined the same way as IDFS but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and CIS of any site). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 7-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    66.19 (62.59 to 69.80)
    79.81 (76.79 to 82.82)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.69

    Secondary: DFS Rate at 8 Years

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    End point title
    		 DFS Rate at 8 Years
    End point description
    DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral DCIS. IDFS event was defined as outlined in the description for IDFS rate OM number 1. 8-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    63.49 (59.80 to 67.18)
    77.14 (73.95 to 80.33)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.7

    Secondary: DFS Rate at 7 Years

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    End point title
    		 DFS Rate at 7 Years
    End point description
    DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral DCIS. IDFS event was defined as outlined in the description for IDFS rate OM number 1. 7-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    66.03 (62.42 to 69.64)
    79.37 (76.33 to 82.42)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.7

    Secondary: Disease-free Survival (DFS) Rate at 3 Years

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    End point title
    		 Disease-free Survival (DFS) Rate at 3 Years
    End point description
    DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral ductal carcinoma in situ (DCIS). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 3-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    76.98 (73.82 to 80.15)
    87.59 (85.15 to 90.03)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.7

    Secondary: OS Rate at 7 Years

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    End point title
    		 OS Rate at 7 Years
    End point description
    OS was defined as the time from randomization to death due to any cause. 7-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    84.38 (81.59 to 87.17)
    89.07 (86.72 to 91.43)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    Comparison groups
    Trastuzumab v Trastuzumab Emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0082
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.91

    Secondary: Overall Survival (OS) Rate at 5 Years

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    End point title
    		 Overall Survival (OS) Rate at 5 Years
    End point description
    OS was defined as the time from randomization to death due to any cause. 5-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 5 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    87.71 (85.20 to 90.22)
    91.40 (89.30 to 93.50)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    Comparison groups
    Trastuzumab v Trastuzumab Emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0082
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.91

    Secondary: OS Rate at 8 Years

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    End point title
    		 OS Rate at 8 Years
    End point description
    OS was defined as the time from randomization to death due to any cause. 8-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    81.91 (78.94 to 84.89)
    87.16 (84.62 to 89.70)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    Comparison groups
    Trastuzumab v Trastuzumab Emtansine
    Number of subjects included in analysis
    1486
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0082
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.91

    Secondary: DRFI Rate at 8 Years

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    End point title
    		 DRFI Rate at 8 Years
    End point description
    DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 8-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    74.28 (70.90 to 77.65)
    83.82 (81.03 to 86.62)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.76

    Secondary: DRFI Rate at 7 Years

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    End point title
    		 DRFI Rate at 7 Years
    End point description
    DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 7-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    76.22 (72.95 to 79.48)
    84.55 (81.82 to 87.27)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.76

    Secondary: Distant Recurrence-free Interval (DRFI) Rate at 3 Years

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    End point title
    		 Distant Recurrence-free Interval (DRFI) Rate at 3 Years
    End point description
    DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated. ITT population included all participants who were randomized to the study regardless of whether they received any study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 131 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: percentage of participants
        number (confidence interval 95%)
    83.26 (80.43 to 86.08)
    89.95 (87.72 to 92.19)
    Statistical analysis title
    		 Trastuzumab vs Trastuzumab Emtansine
    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
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.76

    Secondary: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AE=any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable & unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, whether or not considered related to medicinal product. SAE=any AE that met any given criteria: fatal (i.e. AE causes/leads to death); life-threatening (i.e. AE, in view of investigator, placed the participant at immediate risk of death); required/prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity (i.e. AE results in substantial disruption of participant’s ability to conduct normal life functions); congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; significant medical event in investigator's judgment. SE population=all randomized participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent till end of follow up (up to approximately 131 months)
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    720
    740
    Units: percentage of participants
    number (not applicable)
        AEs
    93.3
    98.8
        SAEs
    8.1
    12.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Hepatotoxicity Events as Adjudicated by the Hepatic Review Committee

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    End point title
    		 Percentage of Participants With Hepatotoxicity Events as Adjudicated by the Hepatic Review Committee
    End point description
    Hepatotoxicity events were summarized by treatment arm. Hepatotoxicity events were assessed using liver function laboratory test (LFT) results which included the analysis of baseline and post-baseline levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), and alkaline phosphatase (ALK). Hepatic events, as adjudicated by the Hepatic Review Committee, are summarized. SE population included all randomized participants who received any amount of study treatment. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 64 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    720
    740
    Units: percentage of participants
        number (not applicable)
    0.1
    0.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Cardiac Events as Adjudicated by the Cardiac Review Committee

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    End point title
    		 Percentage of Participants With Cardiac Events as Adjudicated by the Cardiac Review Committee
    End point description
    Cardiac events were defined as death from cardiac cause or severe congestive heart failure (New York Heart Association [NYHA] Class III or IV) with a decrease in left ventricular ejection fraction (LVEF) of 10 percentage points or more from baseline to an LVEF of < 50%. Other cardiac-related events (e.g., any symptomatic congestive heart failure [CHF] associated with a 10% drop in LVEF to < 50%; asymptomatic declines in LVEF requiring dose delay) were summarized as adjudicated by the Cardiac Review Committee. SE population included all randomized participants who received any amount of study treatment. Percentages have been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to approximately 126 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    720
    740
    Units: percentage of participants
        number (not applicable)
    4.2
    3.1
    No statistical analyses for this end point

    Secondary: Number of Participants Who Discontinued Treatment Due to AEs

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    End point title
    		 Number of Participants Who Discontinued Treatment Due to AEs
    End point description
    An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants were treated for up to 14 cycles (1 cycle = 21 days). SE population included all randomized participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9.6 months
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    720
    740
    Units: participants
    15
    134
    No statistical analyses for this end point

    Secondary: Number of Participants With AEs and SAEs Leading to Death

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    End point title
    		 Number of Participants With AEs and SAEs Leading to Death
    End point description
    AE=any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable & unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, whether or not considered related to medicinal product. SAE=any AE that met any given criteria: fatal (i.e. AE causes/leads to death); life-threatening (i.e. AE, in view of investigator, placed the participant at immediate risk of death); required/prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity (i.e. AE results in substantial disruption of participant’s ability to conduct normal life functions); congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; significant medical event in investigator's judgment. SE population=all randomized participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    From signing of informed consent till end of follow up (up to approximately 131 months)
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    720
    740
    Units: participants
    0
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline 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 in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)
    End point description
    EORTC QLQ-C30 consists of 30 questions which assess 5 functional domains (physical, role, cognitive, emotional & social), a global health status/quality of life (GHS/QoL) scale, 3 symptom scales (fatigue, pain, nausea & vomiting), 5 single items (dyspnea, appetite loss, sleep disturbance, constipation & diarrhea), & a perceived financial impact of the disease item. Most questions used a 4-point scale (1=Not at all - 4=Very much; 2 questions used a 7-point scale [1=very poor - 7=Excellent]). Obtained scores are linearly transformed to a score range of 0-100, where higher scores=greater functioning, greater QoL, or a greater degree of symptoms. A positive change from baseline indicates improvement. ITT population. Number analyzed=number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 5 &11, Follow-up (FU) Month 6, FU Month 12 (1 cycle = 21 days)
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: Appetite Loss (n=624, 645)
    7.9 ( 17.4 )
    7.1 ( 16.4 )
        Cycle 5: Appetite Loss (n=558, 571)
    1.0 ( 18.7 )
    6.5 ( 23.7 )
        Cycle 11: Appetite Loss (n=496, 496)
    -0.5 ( 17.2 )
    2.9 ( 20.2 )
        FU Month 6: Appetite Loss (n=410, 462)
    -1.6 ( 18.3 )
    -1.7 ( 19.9 )
        FU Month 12: Appetite Loss (n=384, 430)
    0.5 ( 20.3 )
    -1.9 ( 20.1 )
        Constipation (n=624, 645)
    9.8 ( 20.2 )
    9.5 ( 19.0 )
        Cycle 5: Constipation (n=558, 571)
    1.0 ( 22.4 )
    4.6 ( 22.6 )
        Cycle 11: Constipation (n=496, 496)
    3.4 ( 23.6 )
    7.3 ( 23.1 )
        FU Month 6: Constipation (n=410, 462)
    4.1 ( 23.7 )
    3.7 ( 23.3 )
        FU Month 12: Constipation (n=384, 430)
    3.2 ( 23.2 )
    4.3 ( 24.6 )
        Baseline: Diarrhea (n=624, 645)
    8.8 ( 17.6 )
    6.4 ( 14.9 )
        Cycle 5: Diarrhea (n=558, 571)
    -1.6 ( 19.3 )
    -1.5 ( 19.5 )
        Cycle 11: Diarrhea (n=496, 496)
    -0.4 ( 21.4 )
    -2.4 ( 17.5 )
        FU Month 6: Diarrhea (n=410, 462)
    -3.4 ( 18.5 )
    -1.9 ( 18.3 )
        FU Month 12: Diarrhea (n=384, 430)
    -2.8 ( 18.9 )
    -1.6 ( 18.4 )
        Baseline: Dyspnea (n=624, 645)
    12.7 ( 20.7 )
    11.0 ( 18.8 )
        Cycle 5: Dyspnea (n=558, 571)
    2.3 ( 21.9 )
    4.1 ( 22.4 )
        Cycle 11: Dyspnea (n=496, 496)
    2.8 ( 21.2 )
    2.7 ( 20.4 )
        FU Month 6: Dyspnea (n=410, 462)
    3.3 ( 22.8 )
    3.8 ( 22.7 )
        FU Month 12: Dyspnea (n=384, 430)
    3.9 ( 24.9 )
    5.3 ( 22.4 )
        Baseline: Fatigue (n=624, 645)
    29.2 ( 21.1 )
    28.0 ( 20.0 )
        Cycle 5: Fatigue (n=558, 571)
    1.1 ( 20.1 )
    5.5 ( 19.7 )
        Cycle 11: Fatigue (n=496, 496)
    1.1 ( 20.5 )
    3.8 ( 21.3 )
        FU Month 6: Fatigue (n=410, 462)
    -1.4 ( 21.9 )
    -0.1 ( 22.2 )
        FU Month 12: Fatigue (n=384, 430)
    -0.1 ( 23.3 )
    -0.1 ( 22.1 )
        Baseline: Financial Difficulties (n=604, 635)
    28.6 ( 33.3 )
    27.6 ( 31.9 )
        Cycle 5: Financial Difficulties (n=530, 548)
    -3.1 ( 26.5 )
    -3.0 ( 28.0 )
        Cycle 11: Financial Difficulties (n=472, 480)
    -5.1 ( 27.6 )
    -1.7 ( 28.7 )
        FU Month 6: Financial Difficulties (n=393, 444)
    -8.4 ( 28.3 )
    -6.5 ( 30.6 )
        FU Month 12: Financial Difficulties (n=367, 413)
    -10.9 ( 30.5 )
    -7.3 ( 31.0 )
        Baseline: Insomnia (n=624, 645)
    30.6 ( 30.8 )
    30.6 ( 29.2 )
        Cycle 5: Insomnia (n=558, 571)
    1.9 ( 28.4 )
    1.3 ( 29.7 )
        Cycle 11: Insomnia (n=494, 494)
    2.4 ( 29.9 )
    1.5 ( 30.3 )
        FU Month 6: Insomnia (n=410, 462)
    1.8 ( 31.3 )
    -0.9 ( 32.1 )
        FU Month 12: Insomnia (n=384, 430)
    0.3 ( 30.4 )
    0.7 ( 31.7 )
        Baseline: Nausea/Vomiting (n=624, 645)
    3.3 ( 9.0 )
    2.8 ( 8.0 )
        Cycle 5: Nausea/Vomiting (n=558, 571)
    1.5 ( 11.2 )
    3.2 ( 12.5 )
        Cycle 11: Nausea/Vomiting (n=496, 496)
    1.3 ( 12.8 )
    3.0 ( 11.8 )
        FU Month 6: Nausea/Vomiting (n=410, 462)
    0.8 ( 10.4 )
    0.2 ( 11.1 )
        FU Month 12:Nausea/Vomiting (n=384,430)
    0.4 ( 10.5 )
    1.2 ( 10.9 )
        Baseline: Pain (n=624, 645)
    22.2 ( 22.2 )
    22.6 ( 22.8 )
        Cycle 5: Pain (n=558, 571)
    0.0 ( 23.2 )
    1.8 ( 23.9 )
        Cycle 11: Pain (n=496, 496)
    0.1 ( 23.1 )
    2.1 ( 24.4 )
        FU Month 6: Pain (n=410, 462)
    -0.3 ( 24.6 )
    -0.5 ( 24.3 )
        FU Month 12: Pain (n=384, 430)
    -1.2 ( 25.6 )
    -0.8 ( 25.4 )
        Baseline: Cognitive Functioning (n=624, 645)
    83.3 ( 20.2 )
    84.4 ( 19.0 )
        Cycle 5: Cognitive Functioning (n=558, 571)
    -3.8 ( 18.4 )
    -4.5 ( 18.7 )
        Cycle 11: Cognitive Functioning (n=496, 496)
    -5.4 ( 21.3 )
    -5.3 ( 19.6 )
        FU Month 6: Cognitive Functioning (n=410, 462)
    -4.1 ( 22.0 )
    -6.1 ( 21.6 )
        FU Month 12: Cognitive Functioning (n=384, 430)
    -4.9 ( 22.2 )
    -6.9 ( 21.7 )
        Baseline: Emotional Functioning (n=624, 645)
    75.0 ( 22.0 )
    75.2 ( 21.2 )
        Cycle 5: Emotional Functioning (n=558, 571)
    -0.4 ( 20.0 )
    -1.3 ( 21.3 )
        Cycle 11:Emotional Functioning (n=496,496)
    -1.0 ( 21.3 )
    0.1 ( 22.0 )
        FU Month 6: Emotional Functioning (n=410, 462)
    -2.9 ( 22.0 )
    -0.8 ( 23.3 )
        FU Month 12: Emotional Functioning (n=384, 430)
    -2.0 ( 22.7 )
    -1.6 ( 23.5 )
        Baseline: Physical Functioning (n=624, 645)
    84.5 ( 15.3 )
    85.8 ( 14.1 )
        Cycle 5: Physical Functioning (n=558, 571)
    0.3 ( 12.9 )
    -1.6 ( 12.7 )
        Cycle 11: Physical Functioning (n=496, 496)
    1.9 ( 14.2 )
    -0.6 ( 14.6 )
        FU Month 6: Physical Functioning (n=410, 462)
    2.8 ( 15.4 )
    0.7 ( 15.1 )
        FU Month 12: Physical Functioning (n=384, 430)
    2.7 ( 14.5 )
    0.8 ( 14.5 )
        Baseline: Role Functioning (n=624, 645)
    77.5 ( 25.0 )
    78.6 ( 23.3 )
        Cycle 5: Role Functioning (n=558, 571)
    2.0 ( 24.3 )
    -0.2 ( 24.1 )
        Cycle 11: Role Functioning (n=496, 496)
    4.0 ( 24.3 )
    0.6 ( 24.5 )
        FU Month 6: Role Functioning (n=410, 462)
    7.4 ( 25.8 )
    3.6 ( 26.7 )
        FU Month 12: Role Functioning (n=384, 430)
    8.0 ( 27.5 )
    4.6 ( 25.5 )
        Baseline: Social Functioning (n=624, 645)
    77.1 ( 24.1 )
    76.8 ( 23.2 )
        Cycle 5: Social Functioning (n=558, 571)
    4.0 ( 22.5 )
    1.6 ( 23.8 )
        Cycle 11: Social Functioning (n=496, 496)
    5.8 ( 24.0 )
    2.5 ( 23.6 )
        FU Month 6: Social Functioning (410, 462)
    8.5 ( 23.7 )
    6.5 ( 26.1 )
        FU Month 12: Social Functioning (n=384, 430)
    9.5 ( 25.1 )
    7.4 ( 26.4 )
        Baseline: Global Health Status (n=624, 645)
    71.2 ( 19.3 )
    71.4 ( 18.0 )
        Cycle 5: Global Health Status (n=558, 571)
    0.6 ( 18.9 )
    -1.9 ( 19.6 )
        Cycle 11: Global Health Status (n=496, 496)
    1.7 ( 17.8 )
    -0.5 ( 19.9 )
        FU Month 6: Global Health Status (n=410, 462)
    2.5 ( 19.3 )
    2.0 ( 19.2 )
        FU Month 12: Global Health Status (n=384, 430)
    3.2 ( 19.5 )
    2.8 ( 20.1 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in EORTC Quality of Life Questionnaire – Breast Cancer (QLQ-BR23)

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    End point title
    		 Change From Baseline in EORTC Quality of Life Questionnaire – Breast Cancer (QLQ-BR23)
    End point description
    EORTC-QLQ-BR23= 23-item breast cancer-specific module that consists of 4 functional scales (body image, sexual enjoyment, sexual functioning, future perspective) & 4 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).Obtained scores are linearly transformed to a score range of 0-100.High score for functional scale=high/better level of functioning/healthy functioning. Higher scores for symptom scales=higher levels of symptoms/problems. For functional scales, positive change from baseline=deterioration in QOL & negative change from baseline=improvement in QOL. For symptom scales, positive change from baseline=improvement in QOL & negative change from baseline=deterioration in QOL.ITT population. Number analyzed=number of participants with data available for analysis. n=unique number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycles 5 &11, Follow-up (FU) Month 6, FU Month 12 (1 cycle = 21 days)
    End point values
    		 Trastuzumab Trastuzumab Emtansine
    Number of subjects analysed
    743
    743
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: Body Image (n=622, 645)
    69.8 ( 28.5 )
    67.5 ( 28.5 )
        Cycle 5: Body Image (n=555, 571)
    1.5 ( 20.5 )
    4.6 ( 22.7 )
        Cycle 11: Body Image (n=493, 495)
    3.4 ( 24.4 )
    5.7 ( 23.9 )
        FU Month 6: Body Image (n=409,462)
    3.6 ( 25.1 )
    7.8 ( 25.8 )
        FU Month 12: Body Image (n=383,428)
    6.2 ( 27.1 )
    6.1 ( 27.2 )
        Baseline:Future Perspective(FP)(n=622,645)
    51.3 ( 31.2 )
    50.1 ( 31.7 )
        Cycle 5: FP (n=551, 571)
    2.6 ( 28.3 )
    6.5 ( 29.9 )
        Cycle 11: FP (n=493, 495)
    6.3 ( 30.0 )
    6.1 ( 31.4 )
        FU Month 6: FP (n=409, 462)
    7.7 ( 33.5 )
    8.1 ( 34.6 )
        Change at FU Month 12: FP (n=383, 428)
    8.1 ( 31.1 )
    8.2 ( 33.0 )
        Baseline: Sexual Enjoyment (n=218,241)
    50.9 ( 28.8 )
    52.3 ( 28.5 )
        Cycle 5: Sexual Enjoyment (n=147, 172)
    2.3 ( 26.4 )
    -1.9 ( 24.6 )
        Cycle 11: Sexual Enjoyment (n=128,137)
    4.4 ( 27.5 )
    4.4 ( 24.5 )
        FU Month 6: Sexual Enjoyment (n=104, 126)
    3.2 ( 28.1 )
    0.3 ( 27.5 )
        Month 12: Sexual Enjoyment (n=95, 114)
    5.6 ( 26.0 )
    1.8 ( 26.2 )
        Baseline: Sexual Function (n=550, 564)
    20.2 ( 23.6 )
    22.0 ( 23.4 )
        Cycle 5: Sexual Function (n=456, 466)
    3.3 ( 20.0 )
    2.3 ( 20.0 )
        Cycle 11: Sexual Function (n=393, 382)
    3.1 ( 20.8 )
    1.9 ( 20.3 )
        FU Month 6: Sexual Function (n=321, 360)
    5.1 ( 23.9 )
    4.3 ( 23.1 )
        FU Month 12: Sexual Function (n=289, 319)
    5.9 ( 23.7 )
    5.2 ( 22.7 )
        Baseline: Arm Symptoms (n=622,645)
    24.6 ( 21.1 )
    24.5 ( 21.0 )
        Cycle 5: Arm Symptoms (n=555, 571)
    -2.8 ( 20.9 )
    -2.6 ( 23.0 )
        Cycle 11: Arm Symptoms (n=493, 495)
    -2.6 ( 21.2 )
    0.2 ( 24.2 )
        FU Month 6: Arm Symptoms (n=409,462)
    -3.0 ( 23.5 )
    -1.3 ( 24.2 )
        FU Month 12: Arm Symptoms (n=383,428)
    -5.7 ( 22.8 )
    -1.5 ( 22.6 )
        Baseline: Breast Symptoms (n=622,645)
    22.7 ( 19.1 )
    21.4 ( 17.9 )
        Cycle 5: Breast Symptoms (n=555,571)
    -1.1 ( 20.3 )
    -1.1 ( 19.1 )
        Cycle 11: Breast Symptoms (n=493,495)
    -3.7 ( 19.8 )
    -0.6 ( 19.5 )
        FU Month 6: Breast Function (n=409,462)
    -6.5 ( 20.0 )
    -2.2 ( 19.7 )
        FU Month 12: Breast Function(n=383,428)
    -8.3 ( 19.9 )
    -3.8 ( 19.2 )
        Baseline: Systemic Therapy SE (n=622,645)
    16.7 ( 13.7 )
    16.9 ( 14.1 )
        Cycle 5:Systemic Therapy SE (n=555,571)
    0.7 ( 13.0 )
    5.5 ( 15.3 )
        Cycle 11:Systemic Therapy SE (n=493,495)
    1.2 ( 12.2 )
    4.2 ( 15.4 )
        FU Month 6:Systemic Therapy SE (n=409,462)
    1.9 ( 13.9 )
    1.1 ( 15.3 )
        FU Month 12:Systemic Therapy SE(n=383,428)
    1.3 ( 13.9 )
    1.4 ( 16.3 )
        Baseline:Upset by Hair Loss(n=77,96)
    40.3 ( 35.6 )
    50.7 ( 38.4 )
        Cycle 5: Upset by Hair Loss (n=13,17)
    -5.1 ( 38.1 )
    -17.6 ( 39.3 )
        Cycle 11:Upset by Hair Loss (n=14,14)
    -28.6 ( 45.0 )
    -14.3 ( 33.9 )
        FU Month 6:Upset by Hair Loss(n=25,22)
    -12.0 ( 47.0 )
    -15.2 ( 42.1 )
        FU Month 12:Upset by Hair Loss(n=23,21)
    -2.9 ( 37.5 )
    -14.3 ( 41.6 )
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Trastuzumab Emtansine

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    End point title
    		 Serum Concentrations of Trastuzumab Emtansine [1]
    End point description
    PK-evaluable population included all participants who received at least 1 dose of trastuzumab emtansine and had at least one evaluable post dose PK sample. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint. 99999=The geometric mean and geometric coefficient of variation were not estimable as the samples were below the limit of quantification. The samples were taken prior to administration of the first dose.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Cycles 1, 2, 4 and 5; 15-30 minutes and 2 hours post-infusion on Cycles 1 and 4; treatment discontinuation/completion visit (up to approximately 64 months) (1 cycle = 21 days)
    Notes
    [1] - 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: This endpoint is reporting data for only the trastuzumab emtansine arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab Emtansine
    Number of subjects analysed
    406
    Units: micrograms per milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        Pre-infusion on Cycle 1 (n=406)
    99999 ( 99999 )
        15-30 minutes post-infusion on Cycle 1 (n=402)
    63.0 ( 101.8 )
        2 hours post-infusion on Cycle 1 (n=388)
    67.4 ( 60.0 )
        Pre-infusion on Cycle 2 (n=383)
    1.69 ( 110.7 )
        Pre-infusion on Cycle 4 (n=379)
    1.73 ( 95.7 )
        15-30 minutes post-infusion on Cycle 4 (n=375)
    68.5 ( 59.4 )
        2 hours post-infusion on Cycle 4 (n=358)
    66.4 ( 71.0 )
        Pre-infusion on Cycle 5 (n=336)
    1.67 ( 99.3 )
        Treatment Completion/Discontinuation (n=323)
    0.323 ( 265.3 )
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1)

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    End point title
    		 Plasma Concentrations of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1) [2]
    End point description
    Concentration of DM1 in plasma was measured through the samples obtained from participants randomized to the trastuzumab emtansine arm. DM1 is an ant-microtubule agent derived from maytansine. In transtuzumab entansine, DM1 is linked to the antibody transtuzumab thus helping the drug to specifically target the HER 2- positive cancer cells. PK trastuzumab emtansine evaluable population. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint. 99999=The geometric mean & geometric coefficient of variation were not estimable as majority of the values were lower than reportable. 9999=The geometric coefficient of variation was not estimable as majority of the values were lower than reportable or zero.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15-30 minutes and 2 hour post-infusion on Cycles 1 and 4 (1 cycle = 21 days)
    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: This endpoint is reporting data for only the trastuzumab emtansine arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab Emtansine
    Number of subjects analysed
    417
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Pre-infusion on Cycle 1 (n=401)
    99999 ( 99999 )
        15-30 minutes post-infusion on Cycle 1 (n=397)
    4.21 ( 57.4 )
        2 hours post-infusion on Cycle 1 (n=387)
    3.44 ( 38.2 )
        Pre-infusion on Cycle 4 (n=361)
    0.372 ( 9999 )
        15-30 minutes post-infusion on Cycle 4 (n=359)
    4.81 ( 48.8 )
        2 hours post-infusion on Cycle 4 (n=347)
    3.70 ( 41.0 )
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Trastuzumab

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    End point title
    		 Serum Concentrations of Trastuzumab [3]
    End point description
    PK-evaluable population included all participants who received at least 1 dose of trastuzumab and had at least one evaluable post dose PK sample. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint. 9999=The geometric mean and geometric coefficient of variation were not estimable as the samples were below the limit of quantification. The samples were taken prior to administration of the first dose.
    End point type
    Secondary
    End point timeframe
    Pre-infusion and 15-30 minutes post-infusion on Cycles 1 and 4; Treatment completion/discontinuation visit (up to approximately 64 months) (1 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: This endpoint is reporting data for only the trastuzumab arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab
    Number of subjects analysed
    404
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        Pre-infusion on Cycle 1 (n=388)
    9999 ( 9999 )
        15-30 minutes post-infusion on Cycle 1 (n=384)
    208 ( 43.1 )
        Pre-infusion on Cycle 4 (n=361)
    64.8 ( 60.6 )
        15-30 minutes post-infusion on Cycle 4 (n=355)
    218 ( 47.2 )
        Treatment Completion/Discontinuation (n=325)
    58.7 ( 86.3 )
    No statistical analyses for this end point

    Secondary: Serum Concentrations of Total Trastuzumab

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    End point title
    		 Serum Concentrations of Total Trastuzumab [4]
    End point description
    Total trastuzumab is the sum of conjugated and unconjugated trastuzumab. Blood and serum samples were obtained from participants randomized to the trastuzumab arm. PK-evaluable population included all participants who received at least 1 dose of trastuzumab and had at least one evaluable post dose PK sample. Number analyzed is the number of participants with data available for analysis. n=unique number of participants out of all the assessed participants with data available for analysis at the specified timepoint. Different participants may have contributed data for each timepoint. 9999=The geometric mean and geometric coefficient of variation were not estimable as the samples were below the limit of quantification. The samples were taken prior to administration of the first dose.
    End point type
    Secondary
    End point timeframe
    Pre-infusion on Days 1, 2, 4 and 5; 15-30 minutes and 2 hours post-infusion on Cycles 1 and 4 (1 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: This endpoint is reporting data for only the trastuzumab arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab
    Number of subjects analysed
    421
    Units: ug/mL
    geometric mean (geometric coefficient of variation)
        Pre-infusion on Cycle 1 (n=390)
    9999 ( 9999 )
        15-30 minutes post-infusion on Cycle 1 (n=418)
    71.8 ( 154.7 )
        2 hours post-infusion on Cycle 1 (n=50)
    81.4 ( 74.3 )
        Pre-infusion on Cycle 2 (n=42)
    7.93 ( 256.8 )
        Pre-infusion on Cycle 4 (n=391)
    13.7 ( 78.0 )
        15-30 minutes post-infusion on Cycle 4 (n=361)
    76.9 ( 46.5 )
        2 hours post-infusion on Cycle 4 (n=37)
    81.5 ( 34.0 )
        Pre-infusion on Cycle 5 (n=31)
    8.90 ( 125.0 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive ADAs to Trastuzumab

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    End point title
    		 Number of Participants With Positive ADAs to Trastuzumab [5]
    End point description
    ADA-positive participants after drug administration were determined for participants exposed to trastuzumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 t.u. greater than the baseline titer result. The total number of participants who developed ADAs to trastuzumab was determined by summing the ADA-positive participants across all timepoints. SE Population included all randomized participants who received any amount of study treatment. Number analyzed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1 and 4, and 3-4 months after last dose of the drug (up to approximately 13.6 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: This endpoint is reporting data for only the trastuzumab arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab
    Number of subjects analysed
    720
    Units: participants
        Baseline (n=386)
    11
        Post-baseline (392)
    15
    No statistical analyses for this end point

    Secondary: Median Duration of Trastuzumab Emtansine Exposure

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    End point title
    		 Median Duration of Trastuzumab Emtansine Exposure [6]
    End point description
    Treatment duration was defined as the time between the first and the last infusion of trastuzumab emtansine. SE population included all randomized participants who received any amount of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 12 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: This endpoint is reporting data for only the trastuzumab emtansine arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab Emtansine
    Number of subjects analysed
    740
    Units: months
        median (full range (min-max))
    10 (1 to 12)
    No statistical analyses for this end point

    Secondary: Number of Participants With Positive Anti-drug Antibodies (ADAs) to Trastuzumab Emtansine

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    End point title
    		 Number of Participants With Positive Anti-drug Antibodies (ADAs) to Trastuzumab Emtansine [7]
    End point description
    ADA-positive participants after drug administration were determined for participants exposed to trastuzumab emtansine. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result. The total number of participants who developed ADAs to trastuzumab emtansine was determined by summing the ADA-positive participants across all timepoints. SE population included all randomized participants who received any amount of study treatment. Number analyzed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycles 1 and 4, and 3-4 months after last dose of the drug (up to approximately 13.6 months)
    Notes
    [7] - 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: This endpoint is reporting data for only the trastuzumab emtansine arm. Hence, statistics for all arms in the baseline period is not reported here.
    End point values
    		 Trastuzumab Emtansine
    Number of subjects analysed
    740
    Units: participants
        Baseline (n=410)
    17
        Post-baseline (n=401)
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of informed consent till the end of follow-up (up to approximately 131 months)
    Adverse event reporting additional description
    SE Population. 1 participant randomized to trastuzumab arm was re-randomized to T-DM1 arm. Another participant received 13 cycles of trastuzumab & 1 of T-DM1. Both these participants were included in the trastuzumab ITT & T-DM1 safety analysis. 1 participant in T-DM1 received 9 cycles of trastuzumab & included in trastuzumab safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Trastuzumab Emtansine
    Reporting group description
    		 -

    Reporting group title
    Trastuzumab
    Reporting group description
    		 -

    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)
    94
    126
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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
    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
    COLON CANCER STAGE I
         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
    Vascular disorders
    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
    EMBOLISM
         subjects affected / exposed
    1 / 740 (0.14%)
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         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
    General disorders and administration site conditions
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    3 / 740 (0.41%)
    1 / 720 (0.14%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         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
    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
    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
    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
    Reproductive system and breast disorders
    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
    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
    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
    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
    HEAVY MENSTRUAL BLEEDING
         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
    Respiratory, thoracic and mediastinal disorders
    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
    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
    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
    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
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         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
    Psychiatric disorders
    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
    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
    Investigations
    PLATELET COUNT DECREASED
         subjects affected / exposed
    10 / 740 (1.35%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    10 / 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
    Injury, poisoning and procedural complications
    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
    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
    SEROMA
         subjects affected / exposed
    0 / 740 (0.00%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         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
    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
    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
    ULNA 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
    POST PROCEDURAL HAEMORRHAGE
         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
    RADIUS 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
    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
    Cardiac disorders
    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
    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
    CARDIAC FAILURE
         subjects affected / exposed
    2 / 740 (0.27%)
    3 / 720 (0.42%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIOGENIC SHOCK
         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
    Nervous system disorders
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    Hepatobiliary disorders
    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
    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
    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
    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
    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
    Skin and subcutaneous tissue disorders
    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
    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
    Renal and urinary disorders
    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
    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
    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
    Infections and infestations
    ENTEROCOLITIS INFECTIOUS
         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
    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
    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
    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
    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
    SKIN 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
    PNEUMONIA
         subjects affected / exposed
    6 / 740 (0.81%)
    2 / 720 (0.28%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         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
    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
    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
    DEVICE RELATED INFECTION
         subjects affected / exposed
    5 / 740 (0.68%)
    0 / 720 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    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
    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
    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
    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
    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
    VASCULAR DEVICE INFECTION
         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
    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
    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
    CELLULITIS
         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
    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
    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%)
    633 / 720 (87.92%)
    Vascular disorders
    LYMPHOEDEMA
         subjects affected / exposed
    36 / 740 (4.86%)
    48 / 720 (6.67%)
         occurrences all number
    36
    51
    HYPERTENSION
         subjects affected / exposed
    42 / 740 (5.68%)
    34 / 720 (4.72%)
         occurrences all number
    59
    38
    HOT FLUSH
         subjects affected / exposed
    94 / 740 (12.70%)
    144 / 720 (20.00%)
         occurrences all number
    98
    152
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    39 / 740 (5.27%)
    14 / 720 (1.94%)
         occurrences all number
    57
    16
    PYREXIA
         subjects affected / exposed
    76 / 740 (10.27%)
    29 / 720 (4.03%)
         occurrences all number
    98
    32
    PAIN
         subjects affected / exposed
    90 / 740 (12.16%)
    92 / 720 (12.78%)
         occurrences all number
    107
    113
    OEDEMA PERIPHERAL
         subjects affected / exposed
    29 / 740 (3.92%)
    52 / 720 (7.22%)
         occurrences all number
    33
    56
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    100 / 740 (13.51%)
    86 / 720 (11.94%)
         occurrences all number
    138
    96
    FATIGUE
         subjects affected / exposed
    363 / 740 (49.05%)
    243 / 720 (33.75%)
         occurrences all number
    456
    276
    Reproductive system and breast disorders
    BREAST PAIN
         subjects affected / exposed
    52 / 740 (7.03%)
    41 / 720 (5.69%)
         occurrences all number
    55
    49
    Respiratory, thoracic and mediastinal disorders
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    37 / 740 (5.00%)
    33 / 720 (4.58%)
         occurrences all number
    39
    36
    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
    225
    30
    DYSPNOEA
         subjects affected / exposed
    62 / 740 (8.38%)
    52 / 720 (7.22%)
         occurrences all number
    69
    57
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    27 / 740 (3.65%)
    42 / 720 (5.83%)
         occurrences all number
    29
    44
    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
    Investigations
    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
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    61 / 740 (8.24%)
    36 / 720 (5.00%)
         occurrences all number
    78
    47
    PLATELET COUNT DECREASED
         subjects affected / exposed
    206 / 740 (27.84%)
    17 / 720 (2.36%)
         occurrences all number
    261
    21
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    210 / 740 (28.38%)
    40 / 720 (5.56%)
         occurrences all number
    255
    44
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    172 / 740 (23.24%)
    41 / 720 (5.69%)
         occurrences all number
    209
    51
    WHITE BLOOD CELL COUNT DECREASED
         subjects affected / exposed
    61 / 740 (8.24%)
    41 / 720 (5.69%)
         occurrences all number
    82
    61
    Injury, poisoning and procedural complications
    RADIATION SKIN INJURY
         subjects affected / exposed
    186 / 740 (25.14%)
    199 / 720 (27.64%)
         occurrences all number
    196
    207
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    69 / 740 (9.32%)
    57 / 720 (7.92%)
         occurrences all number
    77
    61
    PARAESTHESIA
         subjects affected / exposed
    56 / 740 (7.57%)
    40 / 720 (5.56%)
         occurrences all number
    68
    43
    HEADACHE
         subjects affected / exposed
    209 / 740 (28.24%)
    124 / 720 (17.22%)
         occurrences all number
    289
    148
    DYSGEUSIA
         subjects affected / exposed
    57 / 740 (7.70%)
    11 / 720 (1.53%)
         occurrences all number
    58
    12
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    136 / 740 (18.38%)
    50 / 720 (6.94%)
         occurrences all number
    146
    51
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    74 / 740 (10.00%)
    60 / 720 (8.33%)
         occurrences all number
    90
    79
    Eye disorders
    LACRIMATION INCREASED
         subjects affected / exposed
    41 / 740 (5.54%)
    13 / 720 (1.81%)
         occurrences all number
    44
    13
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    125 / 740 (16.89%)
    59 / 720 (8.19%)
         occurrences all number
    151
    66
    DIARRHOEA
         subjects affected / exposed
    91 / 740 (12.30%)
    89 / 720 (12.36%)
         occurrences all number
    117
    116
    DRY MOUTH
         subjects affected / exposed
    100 / 740 (13.51%)
    9 / 720 (1.25%)
         occurrences all number
    109
    9
    NAUSEA
         subjects affected / exposed
    308 / 740 (41.62%)
    93 / 720 (12.92%)
         occurrences all number
    441
    111
    ABDOMINAL PAIN
         subjects affected / exposed
    55 / 740 (7.43%)
    42 / 720 (5.83%)
         occurrences all number
    66
    49
    STOMATITIS
         subjects affected / exposed
    80 / 740 (10.81%)
    25 / 720 (3.47%)
         occurrences all number
    96
    28
    VOMITING
         subjects affected / exposed
    107 / 740 (14.46%)
    37 / 720 (5.14%)
         occurrences all number
    140
    45
    Skin and subcutaneous tissue disorders
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    39 / 740 (5.27%)
    21 / 720 (2.92%)
         occurrences all number
    44
    23
    DRY SKIN
         subjects affected / exposed
    48 / 740 (6.49%)
    36 / 720 (5.00%)
         occurrences all number
    52
    40
    RASH MACULO-PAPULAR
         subjects affected / exposed
    43 / 740 (5.81%)
    26 / 720 (3.61%)
         occurrences all number
    50
    27
    PRURITUS
         subjects affected / exposed
    52 / 740 (7.03%)
    42 / 720 (5.83%)
         occurrences all number
    58
    44
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    87 / 740 (11.76%)
    71 / 720 (9.86%)
         occurrences all number
    99
    82
    MYALGIA
         subjects affected / exposed
    113 / 740 (15.27%)
    80 / 720 (11.11%)
         occurrences all number
    126
    87
    ARTHRALGIA
         subjects affected / exposed
    202 / 740 (27.30%)
    158 / 720 (21.94%)
         occurrences all number
    233
    175
    BONE PAIN
         subjects affected / exposed
    51 / 740 (6.89%)
    35 / 720 (4.86%)
         occurrences all number
    54
    38
    BACK PAIN
         subjects affected / exposed
    53 / 740 (7.16%)
    66 / 720 (9.17%)
         occurrences all number
    57
    73
    MUSCLE SPASMS
         subjects affected / exposed
    33 / 740 (4.46%)
    45 / 720 (6.25%)
         occurrences all number
    36
    45
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    64 / 740 (8.65%)
    37 / 720 (5.14%)
         occurrences all number
    79
    39
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    59 / 740 (7.97%)
    53 / 720 (7.36%)
         occurrences all number
    70
    65
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    65 / 740 (8.78%)
    16 / 720 (2.22%)
         occurrences all number
    74
    19
    HYPOKALAEMIA
         subjects affected / exposed
    48 / 740 (6.49%)
    14 / 720 (1.94%)
         occurrences all number
    61
    20

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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 participants 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 participant 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.
    09 Jul 2014
    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.
    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.
    18 Jun 2021
    Study TDM4788g/BO22589 was finalized, so information about median OS was added. The study completion was extended from 10 years post-FPI to 12 years post-FPI. Scheduled follow-up assessments was updated to collect more OS events. The protocol sections covering the determination of sample size and interim analyses were updated to reflect the extension of the study. The details of the planned interim and final analyses of OS was updated accordingly.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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