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    Clinical Trial Results:
    A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer

    Summary
    EudraCT number
    		 2012-004879-38
    Trial protocol
    		 BE   ES   DE   FR   IE  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    19 Dec 2016
    First version publication date
    19 Dec 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BO28408
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02131064
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Other identifier: TRIO021
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, Roche Trial Information Hotline, +41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    03 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial were to compare the total pathological Complete Response (tpCR) rate (ypT0/is, ypN0) and safety among chemotherapy, Trastuzumab (TCH) + Pertuzumab (P) (Arm A) and Trastuzumab Emtansine (T-DM1) + P (Arm B).
    Protection of trial subjects
    This study was conducted in full conformance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study complied with the requirements of the ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting), and was conducted under a U.S. Investigational New Drug application, complying with Food and Drug Administration (FDA) regulations and applicable local, state, and federal laws.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    United States: 83
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Russian Federation: 61
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Spain: 88
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Taiwan: 42
    Country: Number of subjects enrolled
    Germany: 24
    Worldwide total number of subjects
    444
    EEA total number of subjects
    169
    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)
    398
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 574 participants were screened at 68 sites in 10 countries, of which 444 participants were randomized in two arms: TCH + P (Arm A) and T-DM1 + P (Arm B).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TCH + P
    Arm description
    		 Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab 8 mg/kg (loading dose); and 6 mg/kg (maintenance dose) IV infusion q3w

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin IV infusion at a dose to achieve an AUC of 6 mg*min/mL q3w

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m^2 IV infusion q3w

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    RO4368451
    Other name
    Perjeta®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w

    Arm title
    		 T-DM1 + P
    Arm description
    		 Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trastuzumab Emtansine
    Investigational medicinal product code
    RO5304020
    Other name
    Kadcyla®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab Emtansine 3.6 mg/kg IV infusion q3w

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    RO4368451
    Other name
    Perjeta®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab 840 mg (loading dose); and 420 mg (maintenance dose) IV infusion q3w

    Number of subjects in period 1
    		TCH + P T-DM1 + P
    Started
    221
    223
    Completed
    0
    0
    Not completed
    221
    223
         Consent withdrawn by subject
    6
    14
         Death
    -
    1
         Ongoing
    214
    207
         Unspecified
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TCH + P
    Reporting group description
    		 Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).

    Reporting group title
    T-DM1 + P
    Reporting group description
    		 Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).

    Reporting group values
    		 TCH + P T-DM1 + P Total
    Number of subjects
    		 221 223 444
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.3 ± 11.2 50.5 ± 10.6 -
    Gender categorical
    Units: Subjects
        Female
    		 221 222 443
        Male
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    TCH + P
    Reporting group description
    		 Participants received pertuzumab 840 milligrams (mg) (loading dose) and 420 mg (maintenance dose) intravenous (IV) infusion, trastuzumab 8 milligrams per kilogram (mg/kg) (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 milligrams per square meter (mg/m^2) IV infusion and carboplatin at a dose to achieve an area under the curve (AUC) of 6 milligrams per milliliter* minute (mg/mL*min) IV infusion every 3 weeks (q3w) for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).

    Reporting group title
    T-DM1 + P
    Reporting group description
    		 Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).

    Primary: Percentage of Participants With tpCR Assessed Based on Tumor Samples

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    End point title
    		 Percentage of Participants With tpCR Assessed Based on Tumor Samples
    End point description
    tpCR was assessed by local pathology review on samples taken at surgery following completion of neoadjuvant therapy. tpCR was defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes (that is [i.e.], ypT0/is, ypN0 in the American Joint Committee on Cancer [AJCC] staging system, 7th edition). Percentage of participants with tpCR was reported. Intent-to-treat (ITT) population comprised all randomized participants, whether or not they received any study treatment or completed a full course of study treatment. Participants were analyzed according to their randomized treatment.
    End point type
    Primary
    End point timeframe
    Pre-surgery (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    221
    223
    Units: percentage of participants
        number (confidence interval 95%)
    55.7 (48.84 to 62.32)
    44.4 (37.76 to 51.18)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    95% CI for the difference in tPCR rates between treatment arms was calculated using normal approximation. The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0155 [1]
    Method
    		 Cochran-Mantel-Haenszel Chi-Square
    Parameter type
    		 Difference in tpCR rate
    Point estimate
    -11.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.5
         upper limit
    		 -2.02
    Notes
    [1] - Threshold for significance at 5%

    Secondary: Event-free Survival (EFS) Assessed by Investigator Based on Radiological, Clinical and Histological Assessment

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    End point title
    		 Event-free Survival (EFS) Assessed by Investigator Based on Radiological, Clinical and Histological Assessment
    End point description
    EFS is defined as the time from randomization to disease progression or disease recurrence (local, regional, distant, or contralateral, invasive or non-invasive), or death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization up to disease progression or recurrence or death (up to approximately 45 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [2] - The data for this endpoint will be reported after final analysis.
    [3] - The data for this endpoint will be reported after final analysis.
    No statistical analyses for this end point

    Secondary: Invasive Disease-free Survival (IDFS)

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    End point title
    		 Invasive Disease-free Survival (IDFS)
    End point description
    IDFS is defined only for participants who undergo surgery. Participants who do not undergo surgery will be excluded from the analysis. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast 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, excluding ipsilateral invasive or local-regional breast cancer, in any anatomic site that has been either histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); Contralateral invasive breast cancer; and death from any cause.
    End point type
    Secondary
    End point timeframe
    From surgery to the first documented occurrence of IDFC event (up to approximately 45 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [4] - The data for this endpoint will be reported after final analysis.
    [5] - The data for this endpoint will be reported after final analysis.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as the time from randomization to death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization until death (up to approximately 45 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [6] - The data for this endpoint will be reported after final analysis.
    [7] - The data for this endpoint will be reported after final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Received Breast-Conserving Surgery (BCS)

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    End point title
    		 Percentage of Participants Who Received Breast-Conserving Surgery (BCS)
    End point description
    BCS rate was defined as the percentage of participants who achieve BCS out of the ITT population of participants without inflammatory breast cancer. A subset of ITT population including participants who had non-inflammatory breast cancer at baseline. Participants were analyzed according to their randomized treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    213
    218
    Units: percentage of participants
        number (confidence interval 95%)
    52.6 (45.65 to 59.45)
    41.7 (35.12 to 48.33)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    95% CI for the difference in BCS rate between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in BCS rate
    Point estimate
    -10.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.21
         upper limit
    		 -1.47

    Secondary: Percentage of Participants With Selected Adverse Events (AEs)

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    End point title
    		 Percentage of Participants With Selected Adverse Events (AEs)
    End point description
    Selected AEs included hepatotoxicity, pulmonary toxicity, cardiac dysfunction, neutropenia, thrombocytopenia, peripheral neuropathy, hemorrhage, infusion related reaction (IRR)/hypersensitivity, IRR/hypersensitivity symptoms, rash, diarrhoea and mucositis. Safety population comprised all participants who received at least one full or partial dose of any study treatment. Participants were analyzed according to the treatment they actually received. An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
    End point type
    Secondary
    End point timeframe
    Neoadjuvant phase (Baseline up to Cycle 6, each cycle = 21 days)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    219
    223
    Units: percentage of participants
    number (not applicable)
        Hepatotoxicity
    11.9
    24.2
        Pulmonary Toxicity
    0
    0.9
        Cardiac Dysfunction
    0.9
    0.4
        Neutropenia
    45.2
    0.9
        Thrombocytopenia
    21.9
    7.6
        Peripheral Neuropathy
    30.1
    9.9
        Hemorrhage
    14.6
    20.2
        IRR/Hypersensitivity
    11.9
    17.9
        IRR/Hypersensitivity symptoms
    5.9
    13.9
        Rash
    34.7
    21.5
        Diarrhoea
    73.5
    33.2
        Mucositis
    40.2
    15.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Response for Neuropathy Single Item

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    End point title
    		 Percentage of Participants by Response for Neuropathy Single Item
    End point description
    Participants answered the question “Did you have tingling hands/feet?”, from the Modified Quality of Life Questionnaire Breast Cancer 23 (mQLQ-BR23), on a 4-point scale (1 ‘Not at all’, 2 ‘a little’, 3 ‘quite a bit’ 4 ‘Very much’). Percentage of participants by each response was reported. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = participants evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified categories. Percentage values are based on ITT N.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: percentage of participants
    number (not applicable)
        Not at all: Baseline (n= 194, 205)
    76.9
    80.7
        A little bit: Baseline (n= 194, 205)
    9.5
    10.3
        Somewhat: Baseline (n= 194, 205)
    0
    0
        Quite a bit: Baseline (n= 194, 205)
    0.9
    0.9
        Very much: Baseline (n= 194, 205)
    0.5
    0
        Not at all: Cycle 3 (n= 181, 190)
    55.2
    61.9
        A little bit: Cycle 3 (n= 181, 190)
    20.8
    20.2
        Somewhat: Cycle 3 (n= 181, 190)
    0
    0
        Quite a bit: Cycle 3 (n= 181, 190)
    3.6
    2.7
        Very much: Cycle 3 (n= 181, 190)
    2.3
    0.4
        Not at all: Cycle 5 (n= 181, 182)
    37.1
    55.2
        A little bit: Cycle 5 (n= 181, 182)
    29.9
    22
        Somewhat: Cycle 5 (n= 181, 182)
    0
    0
        Quite a bit: Cycle 5 (n= 181, 182)
    8.1
    2.7
        Very much: Cycle 5 (n= 181, 182)
    6.8
    1.8
        Not at all: Pre-Surgery (n= 172, 176)
    24
    53.4
        A little bit: Pre-Surgery (n= 172, 176)
    28.1
    18.8
        Somewhat: Pre-Surgery (n= 172, 176)
    0
    0
        Quite a bit: Pre-Surgery (n= 172, 176)
    15.8
    5.4
        Very much: Pre-Surgery (n= 172, 176)
    10
    1.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Response for Skin Problem Single Items

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    End point title
    		 Percentage of Participants by Response for Skin Problem Single Items
    End point description
    Participants answered the Question 1 “Did itching skin bother you?” and Question 2 “Have you had skin problems?”, from the mQLQ-BR23, on a 4-point scale (1 ‘Not at all’, 2 ‘a little’, 3 ‘quite a bit’ 4 ‘Very much’). Percentage of participants by each response was reported. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = participants evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified categories. Percentage values are based on ITT N.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: percentage of participants
    number (not applicable)
        Question 1: Not at all: Baseline (n= 193, 205)
    70.6
    72.6
        Question 1: A little bit: Baseline (n= 193, 205)
    14.5
    16.6
        Question 1: Somewhat: Baseline (n= 193, 205)
    0
    0
        Question 1: Quite a bit: Baseline (n= 193, 205)
    2.3
    2.2
        Question 1: Very much: Baseline (n= 193, 205)
    0
    0.4
        Question 1: Not at all: Cycle 3 (n= 180, 190)
    35.3
    50.7
        Question 1: A little bit: Cycle 3 (n= 180, 190)
    32.1
    28.3
        Question 1: Somewhat: Cycle 3 (n= 180, 190)
    0
    0
        Question 1: Quite a bit: Cycle 3 (n= 180, 190)
    11.8
    4.5
        Question 1: Very much: Cycle 3 (n= 180, 190)
    2.3
    1.8
        Question 1: Not at all: Cycle 5 (n= 180, 182)
    48.9
    48
        Question 1: A little bit: Cycle 5 (n= 180, 182)
    22.6
    25.6
        Question 1: Somewhat: Cycle 5 (n= 180, 182)
    0
    0
        Question 1: Quite a bit: Cycle 5 (n= 180, 182)
    7.7
    6.7
        Question 1: Very much: Cycle 5 (n= 180, 182)
    2.3
    1.3
        Question 1: Not at all: Pre-Surgery (n= 172, 176)
    40.7
    49.3
        Question 1:A little bit: Pre-Surgery (n= 172, 176)
    27.1
    22.4
        Question 1: Somewhat: Pre-Surgery (n= 172, 176)
    0
    0
        Question 1: Quite a bit: Pre-Surgery (n= 172, 176)
    7.7
    5.8
        Question 1: Very much: Pre-Surgery (n= 172, 176)
    2.3
    1.3
        Question 2: Not at all: Baseline (n= 194, 205)
    64.3
    66.8
        Question 2: A little bit: Baseline (n= 194, 205)
    19.9
    18.4
        Question 2: Somewhat: Baseline (n= 194, 205)
    0
    0
        Question 2: Quite a bit: Baseline (n= 194, 205)
    3.2
    6.3
        Question 2: Very much: Baseline (n= 194, 205)
    0.5
    0.4
        Question 2: Not at all: Cycle 3 (n= 181, 190)
    13.6
    25.1
        Question 2: A little bit: Cycle 3 (n= 181, 190)
    40.7
    40.4
        Question 2: Somewhat: Cycle 3 (n= 181, 190)
    0
    0
        Question 2: Quite a bit: Cycle 3 (n= 181, 190)
    20.4
    15.2
        Question 2: Very much: Cycle 3 (n= 181, 190)
    7.2
    4.5
        Question 2: Not at all: Cycle 5 (n= 181, 182)
    21.3
    26.9
        Question 2: A little bit: Cycle 5 (n= 181, 182)
    35.7
    37.2
        Question 2: Somewhat: Cycle 5 (n= 181, 182)
    0
    0
        Question 2: Quite a bit: Cycle 5 (n= 181, 182)
    19.9
    13.5
        Question 2: Very much: Cycle 5 (n= 181, 182)
    5
    4
        Question 2: Not at all: Pre-Surgery (n= 172, 176)
    20.8
    28.7
        Question 2:A little bit: Pre-Surgery (n= 172, 176)
    33.9
    37.2
        Question 2: Somewhat: Pre-Surgery (n= 172, 176)
    0
    0
        Question 2: Quite a bit: Pre-Surgery (n= 172, 176)
    16.7
    9
        Question 2: Very much: Pre-Surgery (n= 172, 176)
    6.3
    4
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Response for Hair Loss Single Item

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    End point title
    		 Percentage of Participants by Response for Hair Loss Single Item
    End point description
    Participants answered the Question “Have you lost any hair?”, from the mQLQ-BR23, on a 4-point scale (1 ‘Not at all’, 2 ‘a little’, 3 ‘quite a bit’ 4 ‘Very much’). Percentage of participants by each response was reported. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = participants evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified categories. Percentage values are based on ITT N.
    End point type
    Secondary
    End point timeframe
    Baseline, Cycle 3, Cycle 5 of neoadjuvant period (each cycle = 21 days); pre-surgery visit (within 6 weeks after neoadjuvant therapy; up to approximately 6 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: percentage of participants
    number (not applicable)
        Not at all: Baseline (n= 194, 205)
    79.6
    87.4
        A little bit: Baseline (n= 194, 205)
    7.7
    4.5
        Somewhat: Baseline (n= 194, 205)
    0
    0
        Quite a bit: Baseline (n= 194, 205)
    0.5
    0
        Very much: Baseline (n= 194, 205)
    0
    0
        Not at all: Cycle 3 (n= 181, 190)
    8.6
    67.3
        A little bit: Cycle 3 (n= 181, 190)
    11.8
    17.5
        Somewhat: Cycle 3 (n= 181, 190)
    0
    0
        Quite a bit: Cycle 3 (n= 181, 190)
    20.8
    0.4
        Very much: Cycle 3 (n= 181, 190)
    40.7
    0
        Not at all: Cycle 5 (n= 181, 182)
    20.4
    59.2
        A little bit: Cycle 5 (n= 181, 182)
    19.9
    20.2
        Somewhat: Cycle 5 (n= 181, 182)
    0
    0
        Quite a bit: Cycle 5 (n= 181, 182)
    15.4
    1.8
        Very much: Cycle 5 (n= 181, 182)
    26.2
    0.4
        Not at all: Pre-Surgery (n= 172, 176)
    31.7
    51.6
        A little bit: Pre-Surgery (n= 172, 176)
    12.7
    25.1
        Somewhat: Pre-Surgery (n= 172, 176)
    0
    0
        Quite a bit: Pre-Surgery (n= 172, 176)
    11.3
    2.2
        Very much: Pre-Surgery (n= 172, 176)
    22.2
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score

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    End point title
    		 Percentage of Participants With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score
    End point description
    Participants rated their quality of life (global health status) on European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ- C30), with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Clinically meaningful deterioration in GHS/QoL was defined as a decrease in score of 10 points in GHS/QoL. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = Number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    193
    205
    Units: percentage of participants
        number (not applicable)
    69.9
    45.4
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    95% CI for the difference in clinically meaningful deterioration in GHS/QoL score between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Deterioration
    Point estimate
    -24.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.98
         upper limit
    		 -15.19

    Secondary: Time to Clinically Meaningful Deterioration in GHS/QoL Score

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    End point title
    		 Time to Clinically Meaningful Deterioration in GHS/QoL Score
    End point description
    Participants rated their quality of life (global health status) on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better quality of life. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by GHS/QoL. All valid GHS/QoL questionnaires of the neoadjuvant phase including surgery were used. Participants without deterioration were censored at the time of completing the last GHS/QoL plus 1 day. Median time to deterioration was estimated with Kaplan-Meier method. The 95% confidence interval (CI) for the median was computed using the method of Brookmeyer and Crowley. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = Number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    191
    200
    Units: months
        median (confidence interval 95%)
    3.02 (2.83 to 3.38)
    4.63 (4.11 to 7.98)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified cox proportional hazards regression model was used to estimate Hazard Ratio and CI. Stratification by hormonal receptor status and clinical stage at presentation (stratification factors).
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.78

    Secondary: Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales

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    End point title
    		 Percentage of Participants With a Clinically Meaningful Deterioration in Function Subscales
    End point description
    Participants rated their function on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Clinically meaningful deterioration was defined as a decrease in score of 10 points in physical function and HRQoL; decrease of 7 points in cognitive function and decrease of 14 points in role function. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = Number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    193
    205
    Units: percentage of participants
    number (not applicable)
        Cognitive Functioning
    59.1
    42.4
        Physical Functioning
    72.5
    40
        Role Functioning
    76.7
    47.8
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This is the statistical analysis for cognitive functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Deterioration
    Point estimate
    -16.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.32
         upper limit
    		 -6.94
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    This is the statistical analysis for physical functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Deterioration
    Point estimate
    -32.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.74
         upper limit
    		 -23.34
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    This is the statistical analysis for role functioning. 95% CI for the difference in clinically meaningful deterioration in function subscales between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in Deterioration
    Point estimate
    -28.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.95
         upper limit
    		 -19.8

    Secondary: Time to Clinically Meaningful Deterioration in Function Subscale

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    End point title
    		 Time to Clinically Meaningful Deterioration in Function Subscale
    End point description
    Participants rated their function on EORTC QLQ C-30, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates better functioning. Time to deterioration was defined as the time from baseline to first 10-point (or greater) decrease as measured by physical function; to first 14-point (or greater) decrease as measured by role function, to first 7-point (or greater) decrease as measured by cognitive function. Median time to deterioration was estimated with Kaplan-Meier method. The 95% CI for the median was computed using the method of Brookmeyer and Crowley. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = Number of participants evaluable for this outcome measure. Here, 99999 represents data not estimable.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    191
    200
    Units: months
    median (confidence interval 95%)
        Physical Function
    2.79 (2.79 to 2.96)
    4.86 (4.4 to 7.98)
        Role Function
    2.79 (2.17 to 2.89)
    4.44 (4.04 to 4.53)
        Cognitive Function
    3.42 (3.02 to 4.24)
    4.44 (4.21 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales

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    End point title
    		 Percentage of Participants With a Clinically Meaningful Increase in Symptom Subscales
    End point description
    Participants rated their symptoms on EORTC QLQ C-30 and mQLQ-BR23, with total scores ranging from 0 (worst) to 100 (best); where higher score indicates greater degree of symptoms. Clinically meaningful increase in symptoms was defined as an increase in score (deterioration) of 11 points in nausea and vomiting, pain, dyspnoea; increase of 9 points in insomnia; increase of 14 points in appetite loss; increase of 15 points in diarrhoea, constipation; increase of 10 points in fatigue, systemic therapy side effects, hair loss. ITT population. Participants were analyzed according to their randomized treatment. Number of participants analyzed = Number of participants evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified categories.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: percentage of participants
    number (not applicable)
        Appetitle Loss (n=193, 205)
    61.1
    47.8
        Any Hair Loss (n=194, 205)
    91.2
    40.5
        Systemic Therapy Sise-Effects (n=194, 205)
    89.7
    75.1
        Constipation (n=193, 205)
    33.2
    32.7
        Diarrhoea (n=193, 205)
    79.3
    50.7
        Dyspnea (n=193, 205)
    56
    31.2
        Fatigue (n=193, 205)
    87.6
    68.8
        Nausea/Vomiting (n=193, 205)
    66.3
    43.9
        Pain (n=193, 205)
    56
    36.6
        Insomnia (n=193, 205)
    42.5
    30.2
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Trastuzumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Trastuzumab [8]
    End point description
    Only participants who received trastuzumab were to be analyzed for this outcome. Pharmacokinetic (PK) population comprised all participants who received at least one treatment dose of trastuzumab emtansine (in T-DM1 + P arm) or trastuzumab (in TCH + P arm), and had at least one post-treatment serum or plasma sample. Number of participants analyzed = Number of participants in PK Population evaluable for this outcome. Here ‘n’ signifies number of participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    15-30 minutes (min) post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant period
    Notes
    [8] - 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: Trastuzumab was administered in this arm only.
    End point values
    		 TCH + P
    Number of subjects analysed
    162
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 (n=162)
    167 ± 47.1
        Cycle 6 (n=155)
    148 ± 44.7
    No statistical analyses for this end point

    Secondary: Cmax of Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Cmax of Trastuzumab Emtansine and Total Trastuzumab [9]
    End point description
    Only participants who received trastuzumab emtansine were to be analyzed for this outcome. PK population. Number of participants analyzed = Number of participants in the PK Population evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    15-30 min post-study treatment infusion (infusion duration = 90 min) on Day 1 of Cycle 1 and 6 (each cycle = 21 days) in neoadjuvant period
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trastuzumab emtansine was administered in this arm only.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    207
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Trastuzumab emtansine: Cycle 1 (n=206)
    80.3 ± 26.6
        Trastuzumab emtansine: Cycle 6 (n=179)
    72.3 ± 30
        Total Trastuzumab: Cycle 1 (n=207)
    79 ± 25.7
        Total Trastuzumab: Cycle 6 (n=179)
    79.5 ± 30.9
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Trastuzumab Emtansine and Total Trastuzumab [10]
    End point description
    Only participants who received trastuzumab emtansine were to be analyzed for this outcome. PK population. Number of participants analyzed = Number of participants in the PK population evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    Pre-study treatment infusion (0 hours [hr]) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant period
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trastuzumab emtansine was administered in this arm only.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    191
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Trastuzumab emtansine: (n=190)
    3.06 ± 7.68
        Total Trastuzumab: (n=191)
    12.5 ± 8.9
    No statistical analyses for this end point

    Secondary: Cmin of Trastuzumab

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    End point title
    		 Cmin of Trastuzumab [11]
    End point description
    Only participants who received trastuzumab were to be analyzed for this outcome. PK population. Number of participants analyzed = Number of participants in PK Population with evaluable samples at a given timepoint.
    End point type
    Secondary
    End point timeframe
    Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 6 (cycle length = 21 days) in neoadjuvant period
    Notes
    [11] - 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: Trastuzumab was administered in this arm only.
    End point values
    		 TCH + P
    Number of subjects analysed
    165
    Units: mcg/mL
        arithmetic mean (standard deviation)
    45.8 ± 17.8
    No statistical analyses for this end point

    Secondary: Plasma N2’-Deacetyl-N2’-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations

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    End point title
    		 Plasma N2’-Deacetyl-N2’-(3-mercapto-1-oxopropyl)-Maytansine (DM1) Concentrations [12]
    End point description
    DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome. PK population. Number of participants analyzed = Number of participants in the PK population evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 1 (cycle length = 21 days); 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant period
    Notes
    [12] - 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: Trastuzumab emtansine was administered in this arm only.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    221
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1: Pre-dose (n=211)
    0.0841 ± 0.881
        Cycle 1: 15-30 min post-dose (n=209)
    4.98 ± 2.82
        Cycle 6: 15-30 min post-dose (n=180)
    4.85 ± 2.74
    No statistical analyses for this end point

    Secondary: Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)

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    End point title
    		 Serum Levels of Plasma DM1-Containing Catabolites Concentrations (in ng/mL) (Nonreducible Thioether Linker [MCC]-DM1 and Lysine [Lys]-MCC-DM1)
    End point description
    End point type
    Secondary
    End point timeframe
    Pre-study treatment infusion (0 hr) (infusion duration = 90 min) on Day 1 of Cycle 1 (cycle length = 21 days) in neoadjuvant period; 15-30 min post-study treatment infusion on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: mcg/mL
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [13] - The data for this endpoint will be reported after final analysis.
    [14] - The data for this endpoint will be reported after final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1

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    End point title
    		 Percentage of Participants With Anti-Therapeutic Antibodies (ATA) to TDM-1 [15]
    End point description
    Participants were considered post-baseline ATA positive if they had ATAs post-baseline that were either treatment-induced or treatment-enhanced. Participants had treatment-induced ATAs if they had a negative or missing ATA result at baseline, and at least one positive ATA result post-baseline. Participants had treatment-enhanced ATAs if they had a positive ATA result at baseline, and at least one positive ATA result post-baseline that was greater than or equal to (>/=) 0.60 titer units higher than the result at baseline. ITT population, including participants from T-DM1 + P arm only. Number of participants analyzed = participants evaluable for this outcome measure. Here ‘n’ signifies number of participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-TDM-1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-TDM-1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Trastuzumab emtansine was administered in this arm only.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    216
    Units: percentage of participants
    number (not applicable)
        Neoadjuvant Phase: At Baseline (n=216)
    5.6
        Neoadjuvant Phase: At Post-Baseline (n=201)
    8
    No statistical analyses for this end point

    Secondary: Percentage of Participants With ATA to Trastuzumab

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    End point title
    		 Percentage of Participants With ATA to Trastuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-trastuzumab [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (Pre-trastuzumab infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant period
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: percentage of participants
        number (not applicable)
    Notes
    [16] - The data for this endpoint will be reported after final analysis.
    [17] - The data for this endpoint will be reported after final analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day 1 Cycle 1) to Cycle 6 (each cycle = 21 days) in neoadjuvant period
    Adverse event reporting additional description
    Safety population was analyzed.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    T-DM1 + P
    Reporting group description
    		 Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab emtansine 3.6 mg/kg IV infusion q3w for a total of 18 cycles (6 cycles of neoadjuvant period and 12 cycles of adjuvant period).

    Reporting group title
    TCH + P
    Reporting group description
    		 Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion, trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion, docetaxel 75 mg/m^2 IV infusion and carboplatin at a dose to achieve an AUC of 6 mg/mL*min IV infusion q3w for 6 cycles in neoadjuvant period. Participants received pertuzumab 840 mg (loading dose) and 420 mg (maintenance dose) IV infusion followed by trastuzumab 8 mg/kg (loading dose) and 6 mg/kg (maintenance dose) IV infusion q3w for rest of the cycles (12 cycles) in adjuvant period (up to a total of 18 cycles).

    Serious adverse events
    		 T-DM1 + P TCH + P
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 223 (4.93%)
    63 / 219 (28.77%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast haematoma
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (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
    Pleural effusion
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural intestinal perforation
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 223 (0.45%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 223 (1.35%)
    26 / 219 (11.87%)
         occurrences causally related to treatment / all
    0 / 3
    33 / 33
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    3 / 223 (1.35%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 223 (0.00%)
    7 / 219 (3.20%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 223 (0.45%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 223 (0.00%)
    3 / 219 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 223 (0.00%)
    9 / 219 (4.11%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 223 (0.45%)
    4 / 219 (1.83%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 223 (0.90%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 223 (0.45%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 223 (0.90%)
    0 / 219 (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
    Decreased appetite
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 223 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 223 (0.00%)
    2 / 219 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 T-DM1 + P TCH + P
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 223 (88.79%)
    215 / 219 (98.17%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    17 / 223 (7.62%)
    30 / 219 (13.70%)
         occurrences all number
    20
    32
    Hypertension
         subjects affected / exposed
    10 / 223 (4.48%)
    14 / 219 (6.39%)
         occurrences all number
    10
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    39 / 223 (17.49%)
    57 / 219 (26.03%)
         occurrences all number
    59
    102
    Chills
         subjects affected / exposed
    23 / 223 (10.31%)
    9 / 219 (4.11%)
         occurrences all number
    26
    9
    Fatigue
         subjects affected / exposed
    74 / 223 (33.18%)
    93 / 219 (42.47%)
         occurrences all number
    106
    133
    Influenza like illness
         subjects affected / exposed
    13 / 223 (5.83%)
    6 / 219 (2.74%)
         occurrences all number
    15
    7
    Mucosal inflammation
         subjects affected / exposed
    18 / 223 (8.07%)
    30 / 219 (13.70%)
         occurrences all number
    21
    36
    Oedema peripheral
         subjects affected / exposed
    5 / 223 (2.24%)
    27 / 219 (12.33%)
         occurrences all number
    5
    34
    Pyrexia
         subjects affected / exposed
    30 / 223 (13.45%)
    29 / 219 (13.24%)
         occurrences all number
    41
    39
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    15 / 223 (6.73%)
    9 / 219 (4.11%)
         occurrences all number
    16
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    26 / 223 (11.66%)
    15 / 219 (6.85%)
         occurrences all number
    31
    18
    Epistaxis
         subjects affected / exposed
    35 / 223 (15.70%)
    24 / 219 (10.96%)
         occurrences all number
    62
    29
    Dyspnoea
         subjects affected / exposed
    13 / 223 (5.83%)
    14 / 219 (6.39%)
         occurrences all number
    15
    18
    Oropharyngeal pain
         subjects affected / exposed
    7 / 223 (3.14%)
    11 / 219 (5.02%)
         occurrences all number
    8
    14
    Psychiatric disorders
    Depression
         subjects affected / exposed
    8 / 223 (3.59%)
    14 / 219 (6.39%)
         occurrences all number
    8
    14
    Insomnia
         subjects affected / exposed
    32 / 223 (14.35%)
    29 / 219 (13.24%)
         occurrences all number
    36
    31
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    39 / 223 (17.49%)
    18 / 219 (8.22%)
         occurrences all number
    50
    31
    Alanine aminotransferase increased
         subjects affected / exposed
    52 / 223 (23.32%)
    23 / 219 (10.50%)
         occurrences all number
    65
    33
    Neutrophil count decreased
         subjects affected / exposed
    4 / 223 (1.79%)
    22 / 219 (10.05%)
         occurrences all number
    5
    40
    Platelet count decreased
         subjects affected / exposed
    13 / 223 (5.83%)
    27 / 219 (12.33%)
         occurrences all number
    25
    38
    Weight decreased
         subjects affected / exposed
    13 / 223 (5.83%)
    22 / 219 (10.05%)
         occurrences all number
    13
    22
    White blood cell count decreased
         subjects affected / exposed
    4 / 223 (1.79%)
    15 / 219 (6.85%)
         occurrences all number
    4
    16
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    9 / 223 (4.04%)
    20 / 219 (9.13%)
         occurrences all number
    9
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 223 (8.07%)
    25 / 219 (11.42%)
         occurrences all number
    24
    27
    Dysgeusia
         subjects affected / exposed
    30 / 223 (13.45%)
    43 / 219 (19.63%)
         occurrences all number
    38
    54
    Headache
         subjects affected / exposed
    62 / 223 (27.80%)
    35 / 219 (15.98%)
         occurrences all number
    96
    43
    Hypoaesthesia
         subjects affected / exposed
    5 / 223 (2.24%)
    14 / 219 (6.39%)
         occurrences all number
    6
    15
    Neuropathy peripheral
         subjects affected / exposed
    15 / 223 (6.73%)
    27 / 219 (12.33%)
         occurrences all number
    19
    31
    Paraesthesia
         subjects affected / exposed
    4 / 223 (1.79%)
    19 / 219 (8.68%)
         occurrences all number
    5
    23
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 223 (7.17%)
    22 / 219 (10.05%)
         occurrences all number
    17
    23
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    9 / 223 (4.04%)
    58 / 219 (26.48%)
         occurrences all number
    11
    85
    Anaemia
         subjects affected / exposed
    30 / 223 (13.45%)
    78 / 219 (35.62%)
         occurrences all number
    33
    97
    Thrombocytopenia
         subjects affected / exposed
    16 / 223 (7.17%)
    21 / 219 (9.59%)
         occurrences all number
    18
    27
    Eye disorders
    Dry eye
         subjects affected / exposed
    14 / 223 (6.28%)
    11 / 219 (5.02%)
         occurrences all number
    14
    13
    Lacrimation increased
         subjects affected / exposed
    4 / 223 (1.79%)
    17 / 219 (7.76%)
         occurrences all number
    6
    19
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    18 / 223 (8.07%)
    29 / 219 (13.24%)
         occurrences all number
    24
    38
    Abdominal pain upper
         subjects affected / exposed
    4 / 223 (1.79%)
    18 / 219 (8.22%)
         occurrences all number
    5
    25
    Diarrhoea
         subjects affected / exposed
    83 / 223 (37.22%)
    159 / 219 (72.60%)
         occurrences all number
    157
    354
    Constipation
         subjects affected / exposed
    25 / 223 (11.21%)
    39 / 219 (17.81%)
         occurrences all number
    38
    42
    Dry mouth
         subjects affected / exposed
    23 / 223 (10.31%)
    2 / 219 (0.91%)
         occurrences all number
    29
    2
    Dyspepsia
         subjects affected / exposed
    22 / 223 (9.87%)
    15 / 219 (6.85%)
         occurrences all number
    25
    18
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 223 (3.14%)
    15 / 219 (6.85%)
         occurrences all number
    8
    17
    Nausea
         subjects affected / exposed
    95 / 223 (42.60%)
    132 / 219 (60.27%)
         occurrences all number
    200
    235
    Haemorrhoids
         subjects affected / exposed
    4 / 223 (1.79%)
    14 / 219 (6.39%)
         occurrences all number
    4
    16
    Vomiting
         subjects affected / exposed
    29 / 223 (13.00%)
    68 / 219 (31.05%)
         occurrences all number
    35
    86
    Stomatitis
         subjects affected / exposed
    21 / 223 (9.42%)
    47 / 219 (21.46%)
         occurrences all number
    28
    65
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    31 / 223 (13.90%)
    142 / 219 (64.84%)
         occurrences all number
    31
    145
    Dry skin
         subjects affected / exposed
    27 / 223 (12.11%)
    23 / 219 (10.50%)
         occurrences all number
    28
    28
    Dermatitis acneiform
         subjects affected / exposed
    7 / 223 (3.14%)
    13 / 219 (5.94%)
         occurrences all number
    8
    13
    Nail disorder
         subjects affected / exposed
    6 / 223 (2.69%)
    14 / 219 (6.39%)
         occurrences all number
    6
    15
    Nail discolouration
         subjects affected / exposed
    0 / 223 (0.00%)
    14 / 219 (6.39%)
         occurrences all number
    0
    15
    Pruritus
         subjects affected / exposed
    13 / 223 (5.83%)
    16 / 219 (7.31%)
         occurrences all number
    15
    22
    Rash
         subjects affected / exposed
    42 / 223 (18.83%)
    54 / 219 (24.66%)
         occurrences all number
    55
    70
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 223 (8.52%)
    30 / 219 (13.70%)
         occurrences all number
    24
    41
    Bone pain
         subjects affected / exposed
    4 / 223 (1.79%)
    14 / 219 (6.39%)
         occurrences all number
    4
    22
    Back pain
         subjects affected / exposed
    8 / 223 (3.59%)
    17 / 219 (7.76%)
         occurrences all number
    12
    18
    Muscle spasms
         subjects affected / exposed
    12 / 223 (5.38%)
    7 / 219 (3.20%)
         occurrences all number
    13
    9
    Myalgia
         subjects affected / exposed
    26 / 223 (11.66%)
    29 / 219 (13.24%)
         occurrences all number
    35
    31
    Musculoskeletal pain
         subjects affected / exposed
    7 / 223 (3.14%)
    12 / 219 (5.48%)
         occurrences all number
    7
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 223 (9.87%)
    15 / 219 (6.85%)
         occurrences all number
    24
    18
    Urinary tract infection
         subjects affected / exposed
    9 / 223 (4.04%)
    14 / 219 (6.39%)
         occurrences all number
    12
    16
    Upper respiratory tract infection
         subjects affected / exposed
    16 / 223 (7.17%)
    9 / 219 (4.11%)
         occurrences all number
    17
    9
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    10 / 223 (4.48%)
    20 / 219 (9.13%)
         occurrences all number
    14
    22
    Decreased appetite
         subjects affected / exposed
    26 / 223 (11.66%)
    39 / 219 (17.81%)
         occurrences all number
    31
    46
    Hypomagnesaemia
         subjects affected / exposed
    0 / 223 (0.00%)
    11 / 219 (5.02%)
         occurrences all number
    0
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2014
    - Surgery was to be performed no later than 6 weeks after the last dose of neoadjuvant treatment instead of no later than 9 weeks. - The inclusion criterion was updated to clarify that participants with multifocal tumors must have had all discrete tumors sampled and centrally confirmed as Human Epidermal Growth Factor Receptor 2 (HER2)-positive. - Exclusion criteria were updated to clarify the eligibility of participants with prior breast in situ cancers (lobular carcinoma in situ, ductal carcinoma in situ) and participants who have received prior local and/or systemic therapies for the treatment and prevention of breast cancer. - Language was added to allow for the use of hematopoietic growth factors for primary prophylaxis as per National Comprehensive Cancer Network (NCCN)/European Society for Medical Oncology (ESMO) guidelines at the investigator’s discretion for patients in the TCH + P arm, and to allow for the use hematopoietic growth factors for secondary prophylaxis for participants in either treatment arm. - For participants in the T-DM1 + P arm who receive optional adjuvant chemotherapy, language was included to prohibit treatment with trastuzumab in conjunction with anthracyclines. - Language was added to clarify that any participant diagnosed with drug related interstitial lung disease/pneumonitis must discontinue treatment with trastuzumab emtansine.
    06 Jul 2015
    - To ensure integrity of the benefit-risk assessment in light of evolving data, language regarding the optional adjuvant chemotherapy for participants in the T-DM1 + P arm was updated from stating that adjuvant chemotherapy was allowed, to recommending adjuvant chemotherapy for participants in the T-DM1 + P arm. Clarification was added regarding participants for whom chemotherapy was recommended, including participants who did not achieve tpCR, and had residual tumor less than (>) 1 centimeter (cm) and/or had residual nodal disease. - Language was updated to recommend the use of hematopoietic growth factors for primary prophylaxis for participants in the TCH + P. - An interim evaluation of total pCR rates by the independent Data Monitoring Committee (iDMC) was specified to be performed to further ensure maintenance of a favorable benefit-risk profile. - Language regarding patient-reported outcomes (PROs) was updated to further specify key treatment-related symptoms and the treatment impact for participants with early breast cancer (EBC).

    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.
    The reported results are interim only.
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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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