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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
    29 May 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Jun 2019
    First version publication date
    19 Dec 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BO28408
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Medical Communications, Hoffmann-La Roche, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    29 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    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
    France: 27
    Country: Number of subjects enrolled
    Taiwan: 42
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Spain: 88
    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 65 sites in 10 countries, of which 444 participants were randomized in two arms: Trastuzumab (TCH) + Pertuzumab (P) (Arm A) and Trastuzumab Emtansine (TDM1) + P (Arm B)

    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
    		 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
    		 Experimental

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent 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
    Pertuzumab
    Investigational medicinal product code
    Other name
    Perjeta®, RO4368451
    Pharmaceutical forms
    Concentrate and solvent for 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

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Herceptin®
    Pharmaceutical forms
    Concentrate and solvent 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
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Docetaxel 75 mg/m^2 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
    Other name
    Kadcyla®, RO5304020
    Pharmaceutical forms
    Concentrate and solvent 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
    Other name
    Perjeta®, RO4368451
    Pharmaceutical forms
    Concentrate and solvent for 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
    196
    189
    Not completed
    25
    34
         Adverse event, serious fatal
    5
    6
         Consent withdrawn by subject
    14
    18
         Unspecified
    2
    2
         Lost to follow-up
    4
    8

    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
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 200 198 398
        From 65-84 years
    		 21 25 46
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.3 ± 11.2 50.5 ± 10.6 -
    Sex: Female, Male
    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 Subjects With Total Pathological Complete Response (tpCR) Assessed Based on Tumor Samples

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    End point title
    		 Percentage of Subjects With Total Pathological Complete Response (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 subjects with tpCR was reported.
    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 Subjects
        number (confidence interval 95%)
    56.1 (49.29 to 62.76)
    44.4 (37.76 to 51.18)
    Statistical analysis title
    		 tpCR Analysis
    Statistical analysis description
    95% CI for the difference in tPCR rates between treatment arms was calculated using normal approximation.
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.0126 [2]
    Method
    		 Cochran-Mantel-Haenszel Chi-Square
    Parameter type
    		 Difference in tpCR rate
    Point estimate
    -11.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.95
         upper limit
    		 -2.48
    Notes
    [1] - The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation.
    [2] - Threshold for significance at 5%

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

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    End point title
    		 Percentage of Subjects Who Received Breast-Conserving Surgery (BCS)
    End point description
    BCS rate was defined as the percentage of subjects who achieve BCS out of the ITT population of subjects without inflammatory breast cancer.
    End point type
    Secondary
    End point timeframe
    Surgery performed after completion of neoadjuvant therapy (approximately 6 months after neoadjuvant period)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    213
    218
    Units: Percentage of Subjects
        number (confidence interval 95%)
    52.6 (45.65 to 59.45)
    41.7 (35.12 to 48.33)
    Statistical analysis title
    		 BCS Analysis
    Statistical analysis description
    95% CI for the difference in BCS rate between treatment arms was calculated using normal approximation.
    Comparison groups
    T-DM1 + P v TCH + P
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.0228
    Method
    		 Cochran-Mantel-Haenszel Chi-square Test
    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
    Notes
    [3] - The Cochran-Mantel-Haenszel Chi-square test was used and stratified by local hormone receptor status and clinical stage at presentation.

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

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    End point title
    		 Percentage of Subjects 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, diarrhea and mucositis. 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
    Baseline to end of study (approximately 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    219
    223
    Units: Percentage of Subjects
    number (not applicable)
        Hepatotoxicity
    14.2
    39.0
        Pulmonary Toxicity
    0.9
    4.9
        Cardiac Dysfunction
    4.6
    1.3
        Neutropenia
    39.7
    8.1
        Thrombocytopenia
    22.8
    17.9
        Peripheral Neuropathy
    47.5
    28.7
        Hemorrhage
    19.2
    33.2
        IRR/Hypersensitivity
    13.7
    22.9
        IRR/Hypersensitivity symptoms
    7.8
    19.3
        Rash
    44.7
    36.8
        Diarrhea
    76.7
    38.6
        Mucositis
    43.8
    24.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects by Response for Neuropathy Single Item

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    End point title
    		 Percentage of Subjects by Response for Neuropathy Single Item
    End point description
    Subjects answered the question “Did you have tingling hands/feet?”, from the Modified Quality of Life Questionnaire Breast Cancer 23 (mQLQ-BR23), on a 5-point scale (1 ‘Not at all’, 2 ‘A little’, 3 'Somewhat', 4 ‘Quite a bit’, 5 ‘Very much’). Percentage of subjects by each response was reported.
    End point type
    Secondary
    End point timeframe
    Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: Percentage of Subjects
    number (not applicable)
        Not at all: Baseline
    78.7
    81.2
        A little bit: Baseline
    9.5
    9.4
        Somewhat: Baseline
    0
    0
        Quite a bit: Baseline
    0.9
    0.9
        Very much: Baseline
    0.5
    0
        Not at all: Neoadjuvant Cycle 3
    54.3
    59.6
        A little bit: Neoadjuvant Cycle 3
    20.8
    19.3
        Somewhat: Neoadjuvant Cycle 3
    0
    0
        Quite a bit: Neoadjuvant Cycle 3
    3.2
    2.7
        Very much: Neoadjuvant Cycle 3
    1.8
    0.4
        Not at all: Neoadjuvant Cycle 5
    37.1
    54.3
        A little bit: Neoadjuvant Cycle 5
    29.9
    21.1
        Somewhat: Neoadjuvant Cycle 5
    0
    0
        Quite a bit: Neoadjuvant Cycle 5
    8.6
    2.7
        Very much: Neoadjuvant Cycle 5
    6.8
    1.8
        Not at all: Pre-Surgery
    22.6
    52.0
        A little bit: Pre-Surgery
    29.0
    17.9
        Somewhat: Pre-Surgery
    0
    0
        Quite a bit: Pre-Surgery
    15.4
    5.4
        Very much: Pre-Surgery
    10.0
    1.3
        Not at all: Adjuvant Cycle 4
    31.2
    42.6
        A little bit: Adjuvant Cycle 4
    31.7
    15.2
        Somewhat: Adjuvant Cycle 4
    0
    0
        Quite a bit: Adjuvant Cycle 4
    9.5
    9
        Very much: Adjuvant Cycle 4
    6.3
    2.7
        Not at all: Adjuvant Cycle 8
    33.0
    31.8
        A little bit: Adjuvant Cycle 8
    28.1
    19.3
        Somewhat: Adjuvant Cycle 8
    0
    0
        Quite a bit: Adjuvant Cycle 8
    10.9
    9.0
        Very much: Adjuvant Cycle 8
    4.1
    4.0
        Not at all: End of Therapy
    31.2
    31.4
        A little bit: End of Therapy
    30.8
    23.8
        Somewhat: End of Therapy
    0
    0
        Quite a bit: End of Therapy
    10.9
    12.1
        Very much: End of Therapy
    5.0
    6.7
        Not at all: Follow-up 2
    38.0
    32.7
        A little bit: Follow-up 2
    19.9
    19.3
        Somewhat: Follow-up 2
    0
    0
        Quite a bit: Follow-up 2
    5.9
    7.6
        Very much: Follow-up 2
    4.1
    1.3
        Not at all: Follow-up 4
    39.8
    32.7
        A little bit: Follow-up 4
    15.4
    17.9
        Somewhat: Follow-up 4
    0
    0
        Quite a bit: Follow-up 4
    4.1
    3.1
        Very much: Follow-up 4
    2.3
    1.8
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects by Response for Skin Problem Single Items
    End point description
    Subjects answered the Question 1 “Did itching skin bother you?” and Question 2 “Have you had skin problems?”, from the mQLQ-BR23, on a 5-point scale (1 ‘Not at all’, 2 ‘A little’, 3 'Somewhat', 4 ‘Quite a bit’, 5 ‘Very much’). Percentage of subjects by each response was reported.
    End point type
    Secondary
    End point timeframe
    Baseline,Cycle(C) 3,C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4 (approx 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    193
    205
    Units: Percentage of Subjects
    number (not applicable)
        Q1: Not at all: Baseline
    71.9
    72.6
        Q1: A little bit: Baseline
    14.9
    16.1
        Q1: Somewhat: Baseline
    0
    0
        Q1: Quite a bit: Baseline
    2.3
    2.2
        Q1: Very much: Baseline
    0
    0.4
        Q1: Not at all: Neoadjuvant Cycle 3
    35.3
    48.9
        Q1: A little bit: Neoadjuvant Cycle 3
    31.2
    27.4
        Q1: Somewhat: Neoadjuvant Cycle 3
    0
    0
        Q1: Quite a bit: Neoadjuvant Cycle 3
    10.9
    4.0
        Q1: Very much: Neoadjuvant Cycle 3
    2.3
    1.8
        Q1: Not at all: Neoadjuvant Cycle 5
    48.9
    46.2
        Q1: A little bit: Neoadjuvant Cycle 5
    23.1
    26.0
        Q1: Somewhat: Neoadjuvant Cycle 5
    0
    0
        Q1: Quite a bit: Neoadjuvant Cycle 5
    7.7
    6.3
        Q1: Very much: Neoadjuvant Cycle 5
    2.3
    1.3
        Q1: Not at all: Pre-Surgery
    40.3
    48.0
        Q1: A little bit: Pre-Surgery
    26.7
    21.5
        Q1: Somewhat: Pre-Surgery
    0
    0
        Q1: Quite a bit: Pre-Surgery
    7.2
    5.8
        Q1: Very much: Pre-Surgery
    2.7
    1.3
        Q1: Not at all: Adjuvant Cycle 4
    38.5
    39.0
        Q1: A little bit: Adjuvant Cycle 4
    23.5
    21.5
        Q1: Somewhat: Adjuvant Cycle 4
    0
    0
        Q1: Quite a bit: Adjuvant Cycle 4
    9.5
    6.7
        Q1: Very much: Adjuvant Cycle 4
    6.8
    2.2
        Q1: Not at all: Adjuvant Cycle 8
    34.8
    39.0
        Q1: A little bit: Adjuvant Cycle 8
    27.6
    15.7
        Q1: Somewhat: Adjuvant Cycle 8
    0
    0
        Q1: Quite a bit: Adjuvant Cycle 8
    9.0
    6.3
        Q1: Very much: Adjuvant Cycle 8
    4.1
    3.1
        Q1: Not at all: End of Therapy
    39.4
    42.6
        Q1: A little bit: End of Therapy
    26.7
    22.9
        Q1: Somewhat: End of Therapy
    0
    0
        Q1: Quite a bit: End of Therapy
    6.8
    6.7
        Q1: Very much: End of Therapy
    4.5
    1.8
        Q1: Not at all: Follow-up 2
    43.9
    39.9
        Q1: A little bit: Follow-up 2
    19.0
    14.8
        Q1: Somewhat: Follow-up 2
    0
    0
        Q1: Quite a bit: Follow-up 2
    3.6
    4.0
        Q1: Very much: Follow-up 2
    0.9
    2.2
        Q1: Not at all: Follow-up 4
    46.2
    37.7
        Q1: A little bit: Follow-up 4
    10.4
    12.1
        Q1: Somewhat: Follow-up 4
    0
    0
        Q1: Quite a bit: Follow-up 4
    3.2
    4.5
        Q1: Very much: Follow-up 4
    1.4
    1.3
        Q2: Not at all: Baseline
    64.7
    67.3
        Q2: A little bit: Baseline
    21.3
    17.9
        Q2: Somewhat: Baseline
    0
    0
        Q2: Quite a bit: Baseline
    3.2
    5.8
        Q2: Very much: Baseline
    0.5
    0.4
        Q2: Not at all: Neoadjuvant Cycle 3
    14.0
    24.2
        Q2: A little bit: Neoadjuvant Cycle 3
    40.7
    38.6
        Q2: Somewhat: Neoadjuvant Cycle 3
    0
    0
        Q2: Quite a bit: Neoadjuvant Cycle 3
    18.6
    14.8
        Q2: Very much: Neoadjuvant Cycle 3
    6.8
    4.5
        Q2: Not at all: Neoadjuvant Cycle 5
    21.3
    25.6
        Q2: A little bit: Neoadjuvant Cycle 5
    35.7
    37.7
        Q2: Somewhat: Neoadjuvant Cycle 5
    0
    0
        Q2: Quite a bit: Neoadjuvant Cycle 5
    20.4
    12.6
        Q2: Very much: Neoadjuvant Cycle 5
    5.0
    4.0
        Q2: Not at all: Pre-Surgery
    21.3
    27.4
        Q2: A little bit: Pre-Surgery
    33.9
    37.2
        Q2: Somewhat: Pre-Surgery
    0
    0
        Q2: Quite a bit: Pre-Surgery
    15.4
    8.1
        Q2: Very much: Pre-Surgery
    6.3
    4.0
        Q2: Not at all: Adjuvant Cycle 4
    23.5
    24.2
        Q2: A little bit: Adjuvant Cycle 4
    33.0
    30.9
        Q2: Somewhat: Adjuvant Cycle 4
    0
    0
        Q2: Quite a bit: Adjuvant Cycle 4
    13.1
    9.4
        Q2: Very much: Adjuvant Cycle 4
    9.0
    4.9
        Q2: Not at all: Adjuvant Cycle 8
    23.1
    25.6
        Q2: A little bit: Adjuvant Cycle 8
    35.7
    24.2
        Q2: Somewhat: Adjuvant Cycle 8
    0
    0
        Q2: Quite a bit: Adjuvant Cycle 8
    12.2
    9.9
        Q2: Very much: Adjuvant Cycle 8
    5.0
    4.5
        Q2: Not at all: End of Therapy
    27.1
    27.4
        Q2: A little bit: End of Therapy
    33.9
    30.9
        Q2: Somewhat: End of Therapy
    0
    0
        Q2: Quite a bit: End of Therapy
    10.0
    13.5
        Q2: Very much: End of Therapy
    6.8
    3.1
        Q2: Not at all: Follow-up 2
    36.2
    27.8
        Q2: A little bit: Follow-up 2
    25.8
    25.6
        Q2: Somewhat: Follow-up 2
    0
    0
        Q2: Quite a bit: Follow-up 2
    4.1
    6.3
        Q2: Very much: Follow-up 2
    1.8
    1.3
        Q2: Not at all: Follow-up 4
    39.8
    30.0
        Q2: A little bit: Follow-up 4
    14.5
    18.8
        Q2: Somewhat: Follow-up 4
    0
    0
        Q2: Quite a bit: Follow-up 4
    4.5
    4.5
        Q2: Very much: Follow-up 4
    2.7
    2.2
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects by Response for Hair Loss Single Item
    End point description
    Subjects answered the Question “Have you lost any hair?”, from the mQLQ-BR23, on a 5-point scale (1 ‘Not at all’, 2 ‘A little’, 3 'Somewhat', 4 ‘Quite a bit’, 5 ‘Very much’). Percentage of subjects by each response was reported.
    End point type
    Secondary
    End point timeframe
    Baseline,Cycle(C) 3, C5 of neoadjuvant period (each C=21 days); pre-surgery visit (within 6weeks after neoadjuvant therapy; up to approx 6months), C4 & 8 of Adjuvant Period (each C=21 days), End of Treatment, Follow up 2 & 4(approx 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    194
    205
    Units: Percentage of Subjects
    number (not applicable)
        Not at all: Baseline
    81.4
    87.4
        A little bit: Baseline
    7.7
    4.0
        Somewhat: Baseline
    0
    0
        Quite a bit: Baseline
    0.5
    0
        Very much: Baseline
    0
    0
        Not at all: Neoadjuvant Cycle 3
    8.6
    65.0
        A little bit: Neoadjuvant Cycle 3
    11.3
    16.6
        Somewhat: Neoadjuvant Cycle 3
    0
    0
        Quite a bit: Neoadjuvant Cycle 3
    20.8
    0.4
        Very much: Neoadjuvant Cycle 3
    39.4
    0
        Not at all: Neoadjuvant Cycle 5
    20.4
    58.7
        A little bit: Neoadjuvant Cycle 5
    19.9
    19.3
        Somewhat: Neoadjuvant Cycle 5
    0
    0
        Quite a bit: Neoadjuvant Cycle 5
    15.8
    1.3
        Very much: Neoadjuvant Cycle 5
    26.2
    0.4
        Not at all: Pre-Surgery
    30.8
    49.8
        A little bit: Pre-Surgery
    13.6
    24.7
        Somewhat: Pre-Surgery
    0
    0
        Quite a bit: Pre-Surgery
    11.3
    2.2
        Very much: Pre-Surgery
    21.3
    0
        Not at all: Adjuvant Cycle 4
    67.9
    50.2
        A little bit: Adjuvant Cycle 4
    5.0
    15.7
        Somewhat: Adjuvant Cycle 4
    0
    0
        Quite a bit: Adjuvant Cycle 4
    3.2
    2.2
        Very much: Adjuvant Cycle 4
    2.7
    1.3
        Not at all: Adjuvant Cycle 8
    70.1
    48.9
        A little bit: Adjuvant Cycle 8
    4.1
    14.3
        Somewhat: Adjuvant Cycle 8
    0
    0
        Quite a bit: Adjuvant Cycle 8
    0.9
    0.9
        Very much: Adjuvant Cycle 8
    0.9
    0
        Not at all: End of Therapy
    69.7
    57.8
        A little bit: End of Therapy
    5.4
    14.8
        Somewhat: End of Therapy
    0
    0
        Quite a bit: End of Therapy
    0.9
    0
        Very much: End of Therapy
    1.8
    1.3
        Not at all: Follow-up 2
    55.7
    48.4
        A little bit: Follow-up 2
    9.0
    11.7
        Somewhat: Follow-up 2
    0
    0
        Quite a bit: Follow-up 2
    1.4
    0.4
        Very much: Follow-up 2
    1.8
    0.4
        Not at all: Follow-up 4
    52.9
    41.3
        A little bit: Follow-up 4
    7.2
    11.2
        Somewhat: Follow-up 4
    0
    0
        Quite a bit: Follow-up 4
    0
    2.7
        Very much: Follow-up 4
    1.4
    0.4
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With a Clinically Meaningful Deterioration in Global Health Status (GHS)/Quality of Life (QoL) Score
    End point description
    Subjects 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.
    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 Subjects
        number (not applicable)
    69.9
    45.4
    Statistical analysis title
    		 GHS/QoL Score Analysis
    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
    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.
    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
    		 GHS/QoL Score Analysis
    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
    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 Subjects With a Clinically Meaningful Deterioration in Function Subscales

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    End point title
    		 Percentage of Subjects With a Clinically Meaningful Deterioration in Function Subscales
    End point description
    Subjects rated their function on EORTC QLQ C-30, with total score and single-item (physical, cognitive and role functioning) 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; decrease of 7 points in cognitive function and decrease of 14 points in role function.
    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 Subjects
    number (not applicable)
        Cognitive Functioning
    59.1
    42.4
        Physical Functioning
    72.5
    40.0
        Role Functioning
    76.7
    47.8
    Statistical analysis title
    		 Cognitive Functioning Analysis
    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
    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
    		 Role Functioning Analysis
    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
    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
    Statistical analysis title
    		 Physical Functioning Analysis
    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
    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

    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. 9999 = not estimable value
    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 (4.40 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 9999)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With a Clinically Meaningful Increase in Symptom Subscales
    End point description
    Subjects 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, dyspnea; increase of 9 points in insomnia; increase of 14 points in appetite loss; increase of 15 points in diarrhea, constipation; increase of 10 points in fatigue, systemic therapy side effects, hair loss.
    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 Subjects
    number (not applicable)
        Appetite Loss
    61.1
    47.8
        Any Hair Loss
    91.2
    40.5
        Systemic Therapy Side-Effects
    89.7
    75.1
        Constipation
    33.2
    32.7
        Diarrhea
    79.3
    50.7
        Dyspnea
    56.0
    31.2
        Fatigue
    87.6
    68.8
        Nausea/Vomiting
    66.3
    43.9
        Pain
    56.0
    36.6
        Insomnia
    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 [4]
    End point description
    Only participants who received trastuzumab were to be analyzed for this outcome.
    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 and adjuvant period
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistics reported for this endpoint.
    End point values
    		 TCH + P
    Number of subjects analysed
    214
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 (neoadjuvant period)
    167 ± 47.1
        Cycle 6 (neoadjuvant period)
    148 ± 44.7
        Cycle 1 (adjuvant period)
    159 ± 36.2
        Cycle 6 (adjuvant period)
    181 ± 30.7
    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 [5]
    End point description
    Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
    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 and adjuvant period.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    222
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Trastuzumab emtansine: C1 (neoadjuvant)
    80.4 ± 26.5
        Trastuzumab emtansine: C6 (neoadjuvant)
    71.7 ± 30.2
        Total Trastuzumab: C1 (neoadjuvant)
    79.1 ± 25.7
        Total Trastuzumab: C6 (neoadjuvant)
    79.1 ± 31.1
        Trastuzumab emtansine: C1 (adjuvant)
    70.4 ± 22.7
        Trastuzumab emtansine: C6 (adjuvant)
    73.1 ± 21.8
        Total Trastuzumab: C1 (adjuvant)
    73.0 ± 23.2
        Total Trastuzumab: C6 (adjuvant)
    82.6 ± 23.7
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Trastuzumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) of Trastuzumab [6]
    End point description
    Only participants who received trastuzumab were to be analyzed for this outcome.
    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 and adjuvant period
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: There was no statistics reported for this endpoint.
    End point values
    		 TCH + P
    Number of subjects analysed
    214
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Trastuzumab (neoadjuvant period)
    45.8 ± 17.8
        Trastuzumab (adjuvant period)
    21.8 ± 0.153
    No statistical analyses for this end point

    Secondary: Cmin of Trastuzumab Emtansine and Total Trastuzumab

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    End point title
    		 Cmin of Trastuzumab Emtansine and Total Trastuzumab [7]
    End point description
    Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
    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 and adjuvant period
    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: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    222
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Trastuzumab emtansine (neoadjuvant)
    3.04 ± 7.43
        Total Trastuzumab (neoadjuvant)
    12.3 ± 8.68
        Trastuzumab emtansine (adjuvant)
    4.09 ± 11.7
        Total Trastuzumab (adjuvant)
    8.70 ± 6.98
    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 [8]
    End point description
    DM1 is the metabolite of trastuzumab emtansine. Only participants who received trastuzumab emtansine were to be analyzed for this outcome.
    End point type
    Secondary
    End point timeframe
    15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant 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: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    222
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        C1: 15-30 min post-dose (neoadjuvant)
    4.64 ± 2.33
        C6: 15-30 min post-dose (neoadjuvant)
    4.73 ± 2.61
        C1: 15-30 min post-dose (adjuvant)
    4.49 ± 2.33
        C6: 15-30 min post-dose (adjuvant)
    5.15 ± 8.28
    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) [9]
    End point description
    9999 = not applicable
    End point type
    Secondary
    End point timeframe
    15-30 min post-study treatment infusion (Cmax) on Day 1 of Cycle 1 and 6 in neoadjuvant and adjuvant 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: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    222
    Units: ng/mL
    arithmetic mean (standard deviation)
        C1: MCC-DM1 (Neoadjuvant Period)
    8.18 ± 7.23
        C1: Lys-MCC-DM1 (Neoadjuvant period)
    9999 ± 9999
        C6: MCC-DM1 (Neoadjuvant Period)
    8.22 ± 8.03
        C6: Lys-MCC-DM1 (Neoadjuvant period)
    9999 ± 9999
        C1: MCC-DM1 (Adjuvant Period)
    7.98 ± 6.46
        C1: Lys-MCC-DM1 (Adjuvant period)
    9999 ± 9999
        C6: MCC-DM1 (Adjuvant Period)
    7.90 ± 5.37
        C6: Lys-MCC-DM1 (Adjuvant period)
    9999 ± 9999
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Anti-Therapeutic Antibodies (ATA) to TDM-1 [10]
    End point description
    Subjects were considered post-baseline ATA positive if they had ATAs post-baseline that were either treatment-induced or treatment-enhanced. Subjects had treatment-induced ATAs if they had a negative or missing ATA result at baseline, and at least one positive ATA result post-baseline. Subjects 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.
    End point type
    Secondary
    End point timeframe
    Baseline (b) (Pre-TDM1 [0 hr] infusion [infusion duration = 90 min] on Day 1 of Cycle 1); post-baseline (pb) (Pre-TDM1 infusion [0 hr] on Day 1 of Cycle 6) (each cycle = 21 days) in neoadjuvant and adjuvant 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: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    219
    Units: Percentage of Subjects
    number (not applicable)
        Neoadjuvant Phase (Baseline)
    5.5
        Neoadjuvant Phase (Post-Baseline)
    7.5
        Adjuvant Phase (Baseline)
    11.7
        Adjuvant Phase (Post-baseline)
    13.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With ATA to Trastuzumab

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    End point title
    		 Percentage of Subjects With ATA to Trastuzumab [11]
    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
    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: There was no statistics reported for this endpoint.
    End point values
    		 T-DM1 + P
    Number of subjects analysed
    210
    Units: Percentage of Subjects
    number (not applicable)
        Neoadjuvant Phase (baseline)
    11
        Neoadjuvant Phase (post-baseline)
    2.6
        Adjuvant Phase (baseline)
    5.4
        Adjuvant Phase (post-baseline)
    5.0
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival in the overall study population was defined as the time from the date of randomization to the date of death from any cause. 3 years OS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.
    End point type
    Secondary
    End point timeframe
    From randomization until death or end of study period (up to approximately 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    221
    223
    Units: Probability
        number (confidence interval 95%)
    97.6 (95.5 to 99.7)
    97.0 (94.6 to 99.4)
    Statistical analysis title
    		 Overall Survival
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.7557
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 3.96
    Notes
    [12] - Log Rank was used and stratified by local hormone receptor status and clinical stage at presentation.

    Secondary: Event-free survival (EFS)

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    End point title
    		 Event-free survival (EFS)
    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. 3 years EFS rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.
    End point type
    Secondary
    End point timeframe
    From randomization up to disease progression or recurrence or death (up to approximately 47 months)
    End point values
    		 TCH + P T-DM1 + P
    Number of subjects analysed
    221
    223
    Units: Probability
        number (confidence interval 95%)
    94.21 (91.02 to 97.39)
    85.28 (80.47 to 90.08)
    Statistical analysis title
    		 Event-Free Survival Analysis
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.0027
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.36
         upper limit
    		 4.98
    Notes
    [13] - Log-Rank was used and stratified by local hormone receptor status and clinical stage at presentation.

    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. IDFS is defined as the time from surgery to the first documented occurrence of an IDFS event, defined as: Ipsilateral invasive breast tumor recurrence; Ipsilateral local−regional invasive breast cancer recurrence; Distant recurrence; Contralateral invasive breast cancer; and death from any cause. 3 years of IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after treatment.
    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
    214
    204
    Units: Probability
        number (confidence interval 95%)
    91.99 (86.73 to 97.26)
    93.04 (89.39 to 96.69)
    Statistical analysis title
    		 IDFS Event-Free Analysis
    Comparison groups
    TCH + P v T-DM1 + P
    Number of subjects included in analysis
    418
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 2.4

    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
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    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).

    Serious adverse events
    		 TCH + P T-DM1 + P
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 219 (32.42%)
    30 / 223 (13.45%)
         number of deaths (all causes)
    5
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carinoma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (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
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast haematoma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (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
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Lipase increased
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 219 (1.37%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         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
    2 / 219 (0.91%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 223 (0.45%)
         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
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 219 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    26 / 219 (11.87%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    33 / 33
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    7 / 219 (3.20%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 223 (0.45%)
         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
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 219 (1.37%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    9 / 219 (4.11%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (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
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 219 (1.83%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Nodular regenerative hyperplasia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cellulitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (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
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 219 (0.91%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         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
    1 / 219 (0.46%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 219 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TCH + P T-DM1 + P
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    215 / 219 (98.17%)
    198 / 223 (88.79%)
    Vascular disorders
    Hot flush
    alternative assessment type: Non-systematic
         subjects affected / exposed
    45 / 219 (20.55%)
    22 / 223 (9.87%)
         occurrences all number
    47
    25
    Hypertension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 219 (6.85%)
    14 / 223 (6.28%)
         occurrences all number
    18
    14
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    61 / 219 (27.85%)
    42 / 223 (18.83%)
         occurrences all number
    115
    73
    Chills
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 219 (4.11%)
    27 / 223 (12.11%)
         occurrences all number
    9
    32
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    95 / 219 (43.38%)
    83 / 223 (37.22%)
         occurrences all number
    143
    116
    Influenza like illness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 219 (4.57%)
    16 / 223 (7.17%)
         occurrences all number
    12
    21
    Mucosal inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 219 (13.70%)
    22 / 223 (9.87%)
         occurrences all number
    37
    29
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    31 / 219 (14.16%)
    10 / 223 (4.48%)
         occurrences all number
    38
    11
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    34 / 219 (15.53%)
    38 / 223 (17.04%)
         occurrences all number
    43
    53
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 219 (5.02%)
    6 / 223 (2.69%)
         occurrences all number
    17
    8
    Reproductive system and breast disorders
    Breast pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 219 (5.48%)
    17 / 223 (7.62%)
         occurrences all number
    13
    18
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 219 (9.59%)
    30 / 223 (13.45%)
         occurrences all number
    26
    38
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 219 (8.22%)
    18 / 223 (8.07%)
         occurrences all number
    21
    22
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 219 (10.96%)
    49 / 223 (21.97%)
         occurrences all number
    31
    82
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 219 (5.02%)
    10 / 223 (4.48%)
         occurrences all number
    17
    11
    Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 219 (5.48%)
    11 / 223 (4.93%)
         occurrences all number
    16
    14
    Psychiatric disorders
    Depression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 219 (7.31%)
    10 / 223 (4.48%)
         occurrences all number
    17
    10
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    31 / 219 (14.16%)
    36 / 223 (16.14%)
         occurrences all number
    37
    40
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 219 (6.39%)
    13 / 223 (5.83%)
         occurrences all number
    15
    15
    Investigations
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 219 (10.96%)
    64 / 223 (28.70%)
         occurrences all number
    37
    83
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 219 (9.59%)
    55 / 223 (24.66%)
         occurrences all number
    37
    74
    Neutrophil count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 219 (10.05%)
    5 / 223 (2.24%)
         occurrences all number
    44
    6
    Platelet count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    26 / 219 (11.87%)
    23 / 223 (10.31%)
         occurrences all number
    37
    38
    Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 219 (10.96%)
    18 / 223 (8.07%)
         occurrences all number
    24
    19
    White blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 219 (7.76%)
    8 / 223 (3.59%)
         occurrences all number
    22
    11
    Blood bilirubin increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 219 (0.46%)
    20 / 223 (8.97%)
         occurrences all number
    3
    28
    Injury, poisoning and procedural complications
    Radiation skin injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    46 / 219 (21.00%)
    21 / 223 (9.42%)
         occurrences all number
    48
    22
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 219 (12.33%)
    22 / 223 (9.87%)
         occurrences all number
    30
    28
    Dysgeusia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    44 / 219 (20.09%)
    31 / 223 (13.90%)
         occurrences all number
    58
    39
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    37 / 219 (16.89%)
    68 / 223 (30.49%)
         occurrences all number
    53
    95
    Hypoaesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 219 (8.68%)
    7 / 223 (3.14%)
         occurrences all number
    21
    9
    Neuropathy peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    29 / 219 (13.24%)
    21 / 223 (9.42%)
         occurrences all number
    36
    37
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    23 / 219 (10.50%)
    11 / 223 (4.93%)
         occurrences all number
    28
    14
    Peripheral sensory neuropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    26 / 219 (11.87%)
    26 / 223 (11.66%)
         occurrences all number
    26
    27
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    81 / 219 (36.99%)
    43 / 223 (19.28%)
         occurrences all number
    103
    47
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    59 / 219 (26.94%)
    13 / 223 (5.83%)
         occurrences all number
    92
    20
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 219 (10.96%)
    18 / 223 (8.07%)
         occurrences all number
    36
    23
    Eye disorders
    Dry eye
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 219 (6.39%)
    16 / 223 (7.17%)
         occurrences all number
    16
    16
    Lacrimation increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    18 / 219 (8.22%)
    6 / 223 (2.69%)
         occurrences all number
    21
    9
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    30 / 219 (13.70%)
    21 / 223 (9.42%)
         occurrences all number
    45
    29
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    22 / 219 (10.05%)
    7 / 223 (3.14%)
         occurrences all number
    29
    8
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    43 / 219 (19.63%)
    34 / 223 (15.25%)
         occurrences all number
    48
    52
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    163 / 219 (74.43%)
    86 / 223 (38.57%)
         occurrences all number
    372
    179
    Dry mouth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 219 (1.83%)
    27 / 223 (12.11%)
         occurrences all number
    4
    33
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 219 (6.85%)
    25 / 223 (11.21%)
         occurrences all number
    18
    30
    Gastrooesophageal reflux disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 219 (7.31%)
    7 / 223 (3.14%)
         occurrences all number
    18
    8
    Haemorrhoids
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 219 (6.39%)
    5 / 223 (2.24%)
         occurrences all number
    19
    5
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    139 / 219 (63.47%)
    103 / 223 (46.19%)
         occurrences all number
    249
    248
    Stomatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    49 / 219 (22.37%)
    23 / 223 (10.31%)
         occurrences all number
    70
    30
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    68 / 219 (31.05%)
    35 / 223 (15.70%)
         occurrences all number
    83
    47
    Gingival bleeding
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 219 (0.46%)
    15 / 223 (6.73%)
         occurrences all number
    1
    17
    Skin and subcutaneous tissue disorders
    Alopecia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    146 / 219 (66.67%)
    37 / 223 (16.59%)
         occurrences all number
    149
    38
    Dermatitis acneiform
    alternative assessment type: Non-systematic
         subjects affected / exposed
    16 / 219 (7.31%)
    12 / 223 (5.38%)
         occurrences all number
    16
    14
    Dry skin
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 219 (12.33%)
    30 / 223 (13.45%)
         occurrences all number
    32
    32
    Nail discolouration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 219 (9.13%)
    0 / 223 (0.00%)
         occurrences all number
    21
    0
    Nail disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 219 (5.02%)
    2 / 223 (0.90%)
         occurrences all number
    13
    2
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    26 / 219 (11.87%)
    20 / 223 (8.97%)
         occurrences all number
    34
    22
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    57 / 219 (26.03%)
    43 / 223 (19.28%)
         occurrences all number
    77
    60
    Erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 219 (3.65%)
    16 / 223 (7.17%)
         occurrences all number
    10
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    41 / 219 (18.72%)
    31 / 223 (13.90%)
         occurrences all number
    55
    37
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 219 (9.13%)
    14 / 223 (6.28%)
         occurrences all number
    22
    20
    Bone pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 219 (7.76%)
    8 / 223 (3.59%)
         occurrences all number
    25
    8
    Muscle spasms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 219 (6.39%)
    20 / 223 (8.97%)
         occurrences all number
    16
    21
    Musculoskeletal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 219 (9.13%)
    10 / 223 (4.48%)
         occurrences all number
    22
    10
    Myalgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    37 / 219 (16.89%)
    28 / 223 (12.56%)
         occurrences all number
    41
    42
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 219 (5.94%)
    15 / 223 (6.73%)
         occurrences all number
    16
    15
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    23 / 219 (10.50%)
    29 / 223 (13.00%)
         occurrences all number
    29
    34
    Upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 219 (6.85%)
    21 / 223 (9.42%)
         occurrences all number
    18
    24
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 219 (7.76%)
    12 / 223 (5.38%)
         occurrences all number
    20
    16
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    40 / 219 (18.26%)
    33 / 223 (14.80%)
         occurrences all number
    46
    41
    Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 219 (9.13%)
    13 / 223 (5.83%)
         occurrences all number
    23
    17
    Hypomagnesaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    13 / 219 (5.94%)
    0 / 223 (0.00%)
         occurrences all number
    13
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2014
    Wording regarding the timing between neoadjuvant treatment and surgery was aligned in the protocol synopsis. The Investigational Medicinal Product was updated to provide guidance to refer to national prescribing information for contraindications, adverse reactions, warnings, and precautions for docetaxel and carboplatin. The inclusion and exclusion criteria was updated. The study schema was updated. Language in the Permitted Therapy section was updated. Language was updated in the section with patients receiving optional adjuvant chemotherapy. Language regarding post-study adverse events reporting was updated. Language regarding pulmonary toxicity was clarified. Information regarding potential neurotoxicity was updated and a section on extravasation was added. Clarifications were updated regarding dose modifications/delays in response to trastuzumab emtansine-specific adverse events. Appendix 11 was added to provide guidance on carboplatin dosing for patients for whom the isotope dilution mass spectrometry method of serum creatine measurement is used.

    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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