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    Clinical Trial Results:
    A Randomized, Two-Arm, Open-Label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination with Trastuzumab Plus an Aromatase Inhibitor in First Line Patients with HER2-Positive and Hormone Receptor-Positive Advanced (Metastatic or Locally Advanced) Breast Cancer

    Summary
    EudraCT number
    		 2011-002132-10
    Trial protocol
    		 FR   ES   GB   IT  
    Global end of trial date
    14 Nov 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Nov 2020
    First version publication date
    27 May 2017
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MO27775
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01491737
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124,, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare PFS of pertuzumab given in combination with trastuzumab plus an aromatase inhibitor (AI) versus trastuzumab plus an AI.
    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
    17 Feb 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 60 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 40
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    India: 26
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    Spain: 55
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 40
    Worldwide total number of subjects
    258
    EEA total number of subjects
    135
    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)
    172
    From 65 to 84 years
    81
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 258 subjects were enrolled in the study.

    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
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy
    Arm description
    		 Subjects received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pertuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pertuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 or Day 2 of each subsequent 3 weekly cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent 3 weekly cycle.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole was administered 1 mg once daily.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was administered 2.5 mg once daily.

    Investigational medicinal product name
    Taxane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Taxane was administered (docetaxel every 3 weeks or paclitaxel weekly) in line with the respective product labeling.

    Arm title
    		 Arm B: Trastuzumab + AI +/- Chemotherapy
    Arm description
    		 Subjects received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Trastuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent 3 weekly cycle.

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Anastrozole was administered 1 mg once daily.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Letrozole was administered 2.5 mg once daily.

    Investigational medicinal product name
    Taxane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Taxane was administered (docetaxel every 3 weeks or paclitaxel weekly) in line with the respective product labeling.

    Number of subjects in period 1
    		Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Started
    129
    129
    Received at Least One Dose of Study Drug
    127
    124
    Entered Follow-Up (Post-Treatment)
    120
    116
    Completed
    0
    0
    Not completed
    129
    129
         Consent withdrawn by subject
    20
    17
         Death
    63
    57
         Reason not specified
    8
    9
         Lost to follow-up
    2
    10
         Study Termination by Sponsor
    36
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.

    Reporting group title
    Arm B: Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Subjects received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.

    Reporting group values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy Total
    Number of subjects
    		 129 129 258
    Age categorical
    Units: Subjects
        18-64 Years
    		 86 86 172
        65-84 Years
    		 42 39 81
        85+ Years
    		 1 4 5
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ± 10.85 62.3 ± 11.54 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 129 129 258
        Male
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 10 18 28
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 5 9
        White
    		 104 93 197
        More Than One Race
    		 0 0 0
        Unknown or Not Reported
    		 11 12 23
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 45 40 85
        Chinese
    		 0 0 0
        Indian (Indian subcontinent)
    		 10 16 26
        Japanese
    		 0 1 1
        Mixed Ethnicity
    		 0 0 0
        Other
    		 63 60 123
        Missing
    		 11 12 23
    Number of Subjects by IXRS Stratification Factors
    Subjects were stratified at randomization according to the following factors: -Chosen to receive induction chemotherapy? (Yes vs. No); -Time since adjuvant hormone therapy (<12 months vs. ≥12 months), or no prior hormone therapy. IXRS = interactive response system
    Units: Subjects
        Chemo - Yes and <12 Months Since Hormone Therapy
    		 12 12 24
        Chemo - Yes and ≥12 Months Since Hormone Therapy
    		 24 23 47
        Chemo - Yes and No Prior Hormone Therapy
    		 39 38 77
        Chemo - No and <12 Months Since Hormone Therapy
    		 12 12 24
        Chemo - No and ≥12 Months Since Hormone Therapy
    		 18 19 37
        Chemo - No and No Prior Hormone Therapy
    		 24 25 49

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Subjects received pertuzumab at a loading dose of 840 mg followed by 420 mg along with trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.

    Reporting group title
    Arm B: Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Subjects received trastuzumab at a loading dose of 8 mg/kg of body weight followed by 6 mg/kg of body weight on Day 1 or Day 2 of each 3-weekly cycle until disease progression, unacceptable toxicity, withdrawal of consent, or death, or the predefined end of study whichever occurs first. Participant received aromatase inhibitor (AI), orally as per product labeling (anastrozole: 1 mg once daily or letrozole: 2.5 mg once daily). Subjects receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly), administered in line with the respective product labeling.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    Progression-free survival (PFS) was defined as the time from randomization until the first radiographically documented progression of disease or death from any cause, whichever occurred first (either during study treatment or during follow-up). Progression of disease was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum of target lesion diameters must also demonstrate an absolute increase of at least 5 mm (Note: the appearance of one or more new lesions is also considered progression). Participants with no PFS events were censored at the time of the last evaluable tumor assessment. The primary analysis of PFS was planned to be performed when a total of 165 PFS events had occurred, and the final analysis after at least 60 months follow-up.
    End point type
    Primary
    End point timeframe
    Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    129
    129
    Units: Months
    median (confidence interval 95%)
        Primary Analysis
    18.89 (14.09 to 27.66)
    15.80 (11.04 to 18.56)
        Final Analysis
    20.63 (14.39 to 28.35)
    15.80 (11.04 to 18.66)
    Statistical analysis title
    		 PFS Primary Analysis
    Statistical analysis description
    Log Rank tested the following: Null Hypothesis (H0): the distribution of the PFS time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the PFS time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to PFS was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1.
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.007 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.89
    Notes
    [1] - Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.
    [2] - Test was performed at 2-sided alpha of 5%.
    Statistical analysis title
    		 PFS Final Analysis
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.0059
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.89
    Notes
    [3] - Exploratory. Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) was defined as the time from the date of randomization to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Participants without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and participants with no post-baseline information were censored at the date of randomization. The primary analysis of OS was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants. Here, 999999 indicates median and/or lower and/or upper limits of the 95% confidence interval were not reached because not enough events had occurred at the time of analysis.
    End point type
    Secondary
    End point timeframe
    Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    129
    129
    Units: Months
    median (confidence interval 95%)
        Primary Analysis
    999999 (999999 to 999999)
    999999 (41.40 to 999999)
        Final Analysis
    60.16 (47.21 to 79.01)
    57.17 (45.44 to 999999)
    Statistical analysis title
    		 OS Primary Analysis
    Statistical analysis description
    Exploratory. This study was not powered for overall survival (OS), so adequately powered statistical testing for this outcome measure was not possible.
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.585
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.91
    Notes
    [4] - Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.
    Statistical analysis title
    		 OS Final Analysis
    Statistical analysis description
    Exploratory. This study was not powered for overall survival (OS), so adequately powered statistical testing for this outcome measure was not possible.
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.7833
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.52
    Notes
    [5] - Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    The overall response rate (ORR) was defined as the percentage of participants with best (confirmed) overall response (BOR) of either complete response (CR) or partial response (PR) from start of study treatment until progressive disease (PD)/recurrence or death, as assessed by the investigator according to RECIST version 1.1. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference baseline sum diameters; stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants needed to have two consecutive assessments of PR or CR at least 4 weeks apart to be a responder. Analysis of this outcome measure was only planned to occur at the time of primary analysis.
    End point type
    Secondary
    End point timeframe
    Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    109 [6]
    106 [7]
    Units: Percentage of participants
    number (confidence interval 95%)
        ORR (CR + PR)
    63.3 (53.5 to 72.3)
    55.7 (45.7 to 65.3)
        Non-responders (SD + PD + NE)
    36.7 (27.7 to 46.5)
    44.3 (34.7 to 54.3)
        Complete Response (CR)
    7.3 (3.2 to 14.0)
    0.9 (0.0 to 5.1)
        Partial Response (PR)
    56.0 (46.1 to 65.5)
    54.7 (44.8 to 64.4)
        Stable Disease (SD)
    26.6 (18.6 to 35.9)
    27.4 (19.1 to 36.9)
        Progressive Disease (PD)
    5.5 (2.0 to 11.6)
    12.3 (6.7 to 20.1)
        Not Evaluable (NE)
    4.5 (1.5 to 10.4)
    4.7 (1.5 to 10.7)
    Notes
    [6] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    [7] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    Statistical analysis title
    		 ORR for Arm A vs. Arm B
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2537 [8]
    Method
    		 Chi-squared
    Parameter type
    		 Difference in ORR
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 21.3
    Notes
    [8] - Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment.

    Secondary: Clinical Benefit Response (CBR)

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    End point title
    		 Clinical Benefit Response (CBR)
    End point description
    Clinical Benefit Rate (CBR) was defined as the percentage of participants with best (confirmed) partial response (PR) or complete response (CR) or stable disease (SD) for at least 6 months. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. The ITT population included all randomized participants; this analysis only included participants with measurable disease at baseline. Analysis of this outcome measure was only planned to occur at the time of primary analysis.
    End point type
    Secondary
    End point timeframe
    Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    109 [9]
    106 [10]
    Units: Percentage of participants
    number (confidence interval 95%)
        CBR (CR + PR + SD for ≥6 Months)
    68.8 (59.2 to 77.3)
    67.0 (57.2 to 75.8)
        Complete Response (CR)
    7.3 (3.2 to 14.0)
    0.9 (0.0 to 5.1)
        Partial Response (PR)
    56.0 (46.1 to 65.5)
    54.7 (44.8 to 64.4)
        Stable Disease (SD) for ≥6 Months
    5.5 (2.0 to 11.6)
    11.3 (6.0 to 18.9)
    Notes
    [9] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    [10] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    Statistical analysis title
    		 CBR for Arm A vs. Arm B
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7743 [11]
    Method
    		 Chi-squared
    Parameter type
    		 Difference in CBR
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.2
         upper limit
    		 14.8
    Notes
    [11] - Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment.

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response (DOR) was defined as the period from the date of initial confirmed partial response (PR) or complete response (CR) until the date of progressive disease or death from any cause. According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants with no documented progression after CR or PR were censored at the last date at which they were known to have had the CR or PR, respectively. The primary analysis of DOR was planned to be performed at the same time as for PFS (when a total of 165 PFS events had occurred), and the final analysis was planned after at least 60 months follow-up for all participants. Here, 999999 indicates the upper limit of CI was not reached.
    End point type
    Secondary
    End point timeframe
    Median [full range] of follow-up time on study for: Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B; Final Analysis: 73.20 [0.03-88.34] months vs. 71.06 [0.03-88.97] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    69 [12]
    61 [13]
    Units: Months
    median (confidence interval 95%)
        Primary Analysis (n = 69, 59)
    27.10 (14.13 to 999999)
    15.11 (12.09 to 20.96)
        Final Analysis (n = 69, 61)
    27.40 (15.24 to 44.35)
    16.36 (12.09 to 20.96)
    Notes
    [12] - Number of subjects analyzed: subjects who were responders and had measurable disease at baseline.
    [13] - Number of subjects analyzed: subjects who were responders and had measurable disease at baseline.
    Statistical analysis title
    		 DOR Primary Analysis
    Statistical analysis description
    Log Rank tested the following: Null Hypothesis (H0): the distribution of the DOR time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the DOR time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to DOR was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1.
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0181 [15]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.91
    Notes
    [14] - Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.
    [15] - Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment.
    Statistical analysis title
    		 DOR Final Analysis
    Statistical analysis description
    Exploratory
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0205
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.93
    Notes
    [16] - Stratified log-rank test based upon Kaplan-Meier including the induction chemotherapy and prior adjuvant hormone therapy stratification factors. Hazard ratio comparing Arm A vs. B from stratified Cox proportional hazards model including stratification factors.

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    Time to Response (TTR) was defined as the time from the date of randomization to the date of first complete response (CR) or partial response (PR). According to RECIST version 1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. For participants who did not have a confirmed response, a censored TTR was calculated at the date of the last adequate tumor assessment. If no tumor assessment is performed for the participant (or all post-baseline assessments are not evaluable or PD) the censoring day would be set to day 1 (date of randomization). Analysis of this outcome measure was only planned to occur at the time of primary analysis.
    End point type
    Secondary
    End point timeframe
    Median [full range] of follow-up time on study for Primary Analysis: 31.7 [0.0-44.3] months vs. 30.4 [0.0-45.8] months in Arm A vs. Arm B
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    109 [17]
    106 [18]
    Units: Months
        median (confidence interval 95%)
    2.53 (2.10 to 4.37)
    3.91 (2.10 to 4.17)
    Notes
    [17] - Here, number of subjects analyzed are those who had measurable disease at baseline.
    [18] - Here, number of subjects analyzed are those who had measurable disease at baseline.
    Statistical analysis title
    		 TTR
    Statistical analysis description
    Log Rank tested the following: Null Hypothesis (H0): the distribution of the TTR time was the same in Arms A & B; The Alternative Hypothesis (H1): the distribution of the TTR time was different in Arms A & B. A Cox proportional hazards model tested the HR. If the HR of investigational arm (Arm A) compared with control arm (Arm B) with respect to TTR was assumed to be constant over time (λ) then the null (H0) and alternative hypotheses (H1) were: H0: λ =1; H1: λ ≠1.
    Comparison groups
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy v Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.5597 [20]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 1.57
    Notes
    [19] - The log-rank test from unstratified analysis was based upon Kaplan-Meier approach. Hazard ratio from stratified Cox proportional hazards model including the induction chemotherapy and prior adjuvant hormone therapy stratification factors.
    [20] - Test was performed at 2-sided alpha of 5%. There was no multiplicity adjustment.

    Secondary: Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores

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    End point title
    		 Change From Baseline in Health-Related Quality of Life as Determined by European Quality of Life 5-Dimension (EQ-5D) Visual Analog Scale (VAS) Scores
    End point description
    The EQ-5D VAS is a participant-rated questionnaire to assess health-related quality of life (QoL) in terms of a single index value. The VAS component rates current health state on a scale from 0 mm (worst imaginable health state) to 100 mm (best imaginable health state); higher scores indicate a better health state. The ITT population included all randomised subjects, and only those with non-missing assessments at each timepoint were included in the analysis. In the data table below, ‘n’ indicates the number of subjects who were evaluated at a specified time point; '999999' indicates that the standard deviation could not be calculated because only 1 subject was evaluated at a given timepoint; '9999999' indicates that the mean and standard deviation were not reported because no subjects were evaluated at a given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles (21-day cycle), and every 3 months after treatment discontinuation (up to 49 months, approximately)
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    129
    129
    Units: EQ-5D VAS
    arithmetic mean (standard deviation)
        Baseline (BL) - Value at Visit (n= 98,101)
    73.0 ± 19.34
    72.8 ± 18.83
        Change from BL at Cycle 3 (n= 87, 87)
    3.3 ± 14.90
    1.9 ± 15.67
        Change from BL at Cycle 6 (n= 82, 75)
    3.5 ± 18.91
    0.5 ± 13.63
        Change from BL at Cycle 9 (n= 68, 66)
    5.3 ± 18.80
    2.1 ± 15.20
        Change from BL at Cycle 12 (n= 58, 52)
    10.7 ± 17.91
    4.0 ± 15.34
        Change from BL at Cycle 15 (n= 54, 50)
    9.1 ± 17.25
    1.4 ± 22.16
        Change from BL at Cycle 18 (n= 47, 43)
    7.5 ± 12.85
    3.5 ± 15.76
        Change from BL at Cycle 21 (n= 44, 39)
    5.8 ± 13.68
    3.5 ± 19.70
        Change from BL at Cycle 24 (n= 39, 38)
    6.2 ± 14.30
    3.2 ± 16.66
        Change from BL at Cycle 27 (n= 35, 34)
    7.5 ± 14.01
    3.9 ± 22.00
        Change from BL at Cycle 30 (n= 33, 29)
    8.3 ± 14.25
    4.9 ± 16.98
        Change from BL at Cycle 33 (n= 34, 24)
    5.1 ± 14.70
    4.3 ± 15.59
        Change from BL at Cycle 36 (n= 30, 21)
    7.3 ± 15.19
    5.9 ± 15.13
        Change from BL at Cycle 39 (n= 30, 18)
    8.1 ± 16.33
    2.4 ± 29.68
        Change from BL at Cycle 42 (n= 25, 15)
    6.4 ± 19.18
    9.0 ± 17.55
        Change from BL at Cycle 45 (n= 22, 14)
    9.7 ± 15.01
    9.9 ± 19.52
        Change from BL at Cycle 48 (n= 19, 13)
    8.8 ± 12.50
    6.8 ± 17.22
        Change from BL at Cycle 51 (n= 18, 13)
    7.2 ± 14.81
    9.1 ± 19.11
        Change from BL at Cycle 54 (n= 16, 12)
    4.7 ± 23.48
    7.6 ± 17.85
        Change from BL at Cycle 57 (n= 16, 11)
    6.8 ± 18.08
    10.5 ± 16.81
        Change from BL at Cycle 60 (n= 16, 11)
    8.2 ± 15.88
    10.9 ± 18.27
        Change from BL at Cycle 63 (n= 16, 10)
    4.0 ± 20.88
    8.8 ± 14.64
        Change from BL at Cycle 66 (n= 14, 8)
    10.4 ± 16.92
    4.1 ± 15.69
        Change from BL at Cycle 69 (n= 13, 7)
    7.5 ± 17.35
    5.0 ± 16.77
        Change from BL at Cycle 72 (n= 13, 8)
    6.2 ± 16.10
    5.8 ± 16.10
        Change from BL at Cycle 75 (n= 11, 7)
    8.6 ± 19.12
    5.1 ± 15.50
        Change from BL at Cycle 78 (n= 11, 7)
    12.8 ± 17.45
    6.9 ± 14.58
        Change from BL at Cycle 81 (n= 11, 6)
    11.5 ± 18.39
    8.0 ± 14.76
        Change from BL at Cycle 84 (n= 11, 6)
    11.2 ± 19.71
    1.3 ± 18.13
        Change from BL at Cycle 87 (n= 11, 4)
    11.2 ± 18.17
    -3.0 ± 11.22
        Change from BL at Cycle 90 (n= 11, 4)
    10.9 ± 18.28
    -3.0 ± 12.36
        Change from BL at Cycle 93 (n= 11, 5)
    7.1 ± 15.43
    6.6 ± 13.89
        Change from BL at Cycle 96 (n= 8, 5)
    7.5 ± 16.04
    8.6 ± 12.64
        Change from BL at Cycle 99 (n= 9, 5)
    4.4 ± 17.22
    5.6 ± 16.71
        Change from BL at Cycle 102 (n= 8, 3)
    5.6 ± 16.35
    10.0 ± 17.32
        Change from BL at Cycle 105 (n= 8, 1)
    4.4 ± 16.35
    0.0 ± 999999
        Change from BL at Cycle 108 (n= 7, 1)
    4.0 ± 14.39
    0.0 ± 999999
        Change from BL at Cycle 111 (n= 4, 0)
    3.3 ± 21.50
    9999999 ± 9999999
        Change from BL at Cycle 114 (n= 4, 0)
    -1.3 ± 17.97
    9999999 ± 9999999
        Change from BL at Cycle 117 (n= 1, 0)
    -5.0 ± 999999
    9999999 ± 9999999
        Change from BL at Cycle 120 (n= 1, 0)
    -5.0 ± 999999
    9999999 ± 9999999
    No statistical analyses for this end point

    Secondary: Overview of the Percentage of Participants With Adverse Events, Severity Determined According to NCI-CTCAE version 4.03

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    End point title
    		 Overview of the Percentage of Participants With Adverse Events, Severity Determined According to NCI-CTCAE version 4.03
    End point description
    The safety population was analyzed for all adverse events (AEs) occurring during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication; thereafter, only study drug-related serious adverse events (SAEs) continued to be collected. The investigator graded all AEs for severity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03; if not listed, the AE was assessed as follows: Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening/disabling; Grade 5 = death. The investigator determined whether an AE was related to study drug and independently assessed severity and seriousness of each AE. AEs suggestive of congestive heart failure (CHF) were identified by the SMQ (wide) “Cardiac Failure” with a status of “serious”, which included the preferred terms cardiac failure, left ventricular dysfunction, and pulmonary oedema.
    End point type
    Secondary
    End point timeframe
    From Baseline until the end of post-treatment follow-up (up to 89 months)
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    127
    124
    Units: percentage of subjects
    number (not applicable)
        Any Adverse Event (AE)
    96.1
    98.4
        Any AE, Grade ≥3
    56.7
    41.1
        Any Serious Adverse Event (SAE), Grade ≥3
    27.6
    17.7
        Any AE, Grade 5
    0.8
    0.8
        Any SAE
    36.2
    22.6
        SAE Related to Pertuzumab
    7.9
    0
        SAE Related to Trastuzumab
    7.1
    1.6
        SAE Related to Docetaxel (n = 74, 69)
    8.1
    5.8
        SAE Related to Paclitaxel (n = 74, 69)
    4.1
    0
        Any AE Leading to Discontinuation of Any Treatment
    15.7
    8.1
        Any AE Leading to Pertuzumab Discontinuation
    12.6
    0
        Any AE Leading to Trastuzumab Discontinuation
    12.6
    4.8
        Any AE Leading to Interruption of Any Treatment
    46.5
    21.0
        Any AE Leading to Pertuzumab Interruption
    34.6
    0
        Any AE Leading to Trastuzumab Interruption
    37.8
    12.9
        Any AE Related to Pertuzumab
    64.6
    0
        Any AE Related to Trastuzumab
    63.8
    50
        AE Suggestive of Congestive Heart Failure
    3.9
    0.8
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment

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    End point title
    		 Number of Participants Who Died Over the Course of the Study by Reported Cause of Death and Time of Death Relative to First or Last Dose of Study Treatment
    End point description
    The causes of death over the course of the study, regardless of whether the death was related to study treatment, are listed by preferred term according to the Medical Dictionary for Regulatory Activities (MedDRA), version 22.1.
    End point type
    Secondary
    End point timeframe
    From Baseline until the end of post-treatment follow-up (up to 89 months)
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    127
    124
    Units: Participants
        Total Number of Deaths
    62
    57
        Deaths Related to Any Study Treatment
    0
    0
        Cause of Death: Cardiac Arrest
    1
    0
        Cause of Death: Craniocerebral Injury
    1
    0
        Cause of Death: Dyspnoea
    1
    0
        Cause of Death: High-grade B-cell Lymphoma
    1
    0
        Cause of Death: Sudden Death
    0
    1
        Cause of Death: Unevaluable Event
    2
    1
        Cause of Death: Progressive Disease
    56
    55
        Total Deaths Within 30 Days After First Dose
    0
    0
        Total Deaths Within 28 Days After Last Dose
    1
    2
        Total Deaths Within 60 Days After Last Dose
    2
    4
    No statistical analyses for this end point

    Secondary: Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study

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    End point title
    		 Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Values Over the Course of the Study
    End point description
    Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan. All participants must have had a baseline LVEF of at least (≥)50% to enroll in the study; patients with clinically significant cardiovascular disease or baseline LVEF below 50% were not eligible for this study.
    End point type
    Secondary
    End point timeframe
    Baseline and every 3 cycles until treatment discontinuation (up to Cycle 120; 1 cycle is 21 days)
    End point values
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Number of subjects analysed
    127
    124
    Units: Percentage points of LVEF
    arithmetic mean (standard deviation)
        Baseline (BL) - Absolute LVEF at Visit (n=127,123)
    63.8 ± 6.23
    63.9 ± 6.12
        Change from BL at Cycle 3 (n=114,114)
    -1.0 ± 6.25
    -1.4 ± 6.23
        Change from BL at Cycle 6 (n=101,101)
    -2.3 ± 6.66
    -1.3 ± 6.03
        Change from BL at Cycle 9 (n=87,84)
    -2.5 ± 6.80
    -2.2 ± 6.52
        Change from BL at Cycle 12 (n=75,69)
    -2.4 ± 8.05
    -2.8 ± 6.99
        Change from BL at Cycle 15 (n=64,61)
    -2.9 ± 8.67
    -2.5 ± 6.94
        Change from BL at Cycle 18 (n=62,54)
    -1.9 ± 6.42
    -1.3 ± 6.19
        Change from BL at Cycle 21 (n=53,48)
    -1.1 ± 6.01
    -1.1 ± 6.64
        Change from BL at Cycle 24 (n=52,46)
    -2.1 ± 6.82
    -0.6 ± 6.19
        Change from BL at Cycle 27 (n=46,39)
    -1.6 ± 5.05
    -1.3 ± 5.87
        Change from BL at Cycle 30 (n=43,34)
    -1.4 ± 5.20
    -0.3 ± 6.03
        Change from BL at Cycle 33 (n=44,28)
    -2.8 ± 5.60
    1.2 ± 6.71
        Change from BL at Cycle 36 (n=37,24)
    -2.5 ± 5.50
    -0.2 ± 5.41
        Change from BL at Cycle 39 (n=38,23)
    -2.6 ± 5.72
    1.4 ± 4.87
        Change from BL at Cycle 42 (n=35,18)
    -2.1 ± 5.91
    1.9 ± 6.12
        Change from BL at Cycle 45 (n=31,17)
    -1.0 ± 5.54
    3.0 ± 5.27
        Change from BL at Cycle 48 (n=28,18)
    -3.3 ± 6.56
    -0.2 ± 7.50
        Change from BL at Cycle 51 (n=27,18)
    -1.4 ± 5.82
    1.0 ± 4.19
        Change from BL at Cycle 54 (n=26,13)
    -1.3 ± 6.17
    -1.0 ± 6.23
        Change from BL at Cycle 57 (n=26,15)
    -1.7 ± 6.43
    0.8 ± 5.68
        Change from BL at Cycle 60 (n=25,14)
    -2.5 ± 5.54
    -0.9 ± 3.91
        Change from BL at Cycle 63 (n=26,14)
    -2.1 ± 6.10
    0.8 ± 5.99
        Change from BL at Cycle 66 (n=22,13)
    -2.9 ± 7.80
    -0.4 ± 5.17
        Change from BL at Cycle 69 (n=19,9)
    -2.1 ± 7.23
    -1.5 ± 7.68
        Change from BL at Cycle 72 (n=18,12)
    -3.0 ± 4.97
    -1.0 ± 5.75
        Change from BL at Cycle 75 (n=17,12)
    -3.3 ± 6.59
    -1.1 ± 6.97
        Change from BL at Cycle 78 (n=17,9)
    -3.3 ± 5.58
    -1.1 ± 7.82
        Change from BL at Cycle 81 (n=17,9)
    -2.9 ± 6.83
    -2.6 ± 6.00
        Change from BL at Cycle 84 (n=15,9)
    -2.5 ± 7.66
    -4.5 ± 3.59
        Change from BL at Cycle 87 (n=15,8)
    -3.8 ± 5.76
    -1.4 ± 5.12
        Change from BL at Cycle 90 (n=16,7)
    -2.4 ± 7.69
    0.4 ± 6.77
        Change from BL at Cycle 93 (n=14,7)
    -1.8 ± 6.57
    -3.9 ± 6.00
        Change from BL at Cycle 96 (n=12,7)
    -0.7 ± 7.45
    -3.2 ± 5.50
        Change from BL at Cycle 99 (n=11,7)
    -3.4 ± 5.78
    -2.8 ± 8.41
        Change from BL at Cycle 102 (n=13,5)
    -1.3 ± 6.12
    -1.6 ± 9.68
        Change from BL at Cycle 105 (n=12,3)
    -0.4 ± 7.05
    -2.0 ± 12.17
        Change from BL at Cycle 108 (n=9,3)
    -3.4 ± 5.32
    -3.3 ± 8.33
        Change from BL at Cycle 111 (n=4,1)
    -6.3 ± 5.91
    -5.5 ± 999999
        Change from BL at Cycle 114 (n=4,1)
    -4.0 ± 5.35
    9999999 ± 9999999
        Change from BL at Cycle 117 (n=1,0)
    -11.0 ± 999999
    9999999 ± 9999999
        Change from BL at Cycle 120 (n=1,0)
    -11.0 ± 999999
    9999999 ± 9999999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline until end of post-treatment follow-up (up to 89 months)
    Adverse event reporting additional description
    All adverse events that occurred during the study and until the post-treatment safety follow-up visit approximately 28 days after last study medication were to be recorded. Thereafter, only serious adverse events thought to be related to study drug were collected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Pertuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 840 mg, followed by 420 mg on Day 1 or Day 2 of each subsequent 3 weekly cycle. Trastuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent 3 weekly cycle. An AI (oral) was to be administered in line with product labeling (anastrozole: 1 mg once daily; letrozole: 2.5 mg once daily). Patients receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly),administered in line with the respective product labeling.

    Reporting group title
    Arm B: Trastuzumab + AI +/- Chemotherapy
    Reporting group description
    		 Trastuzumab was administered as an intravenous infusion on Day 1 or Day 2 of the first treatment cycle as a loading dose of 8 mg/kg, followed by 6 mg/kg on Day 1 or Day 2 of each subsequent 3 weekly cycle. An AI (oral) was to be administered in line with product labeling (anastrozole: 1 mg once daily; letrozole: 2.5 mg once daily). Patients receiving induction chemotherapy up to the first 18-24 weeks of the treatment period were to receive a taxane (docetaxel every 3 weeks or paclitaxel weekly),administered in line with the respective product labeling.

    Serious adverse events
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 127 (36.22%)
    28 / 124 (22.58%)
         number of deaths (all causes)
    62
    57
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoid cystic carcinoma of salivary gland
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High-grade B-cell lymphoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour exudation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Colostomy closure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (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
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Painful respiration
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 127 (1.57%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    4 / 127 (3.15%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    4 / 127 (3.15%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    4 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 127 (1.57%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal haemorrhage
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 127 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 127 (2.36%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 127 (4.72%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (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
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 127 (0.79%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Pertuzumab + Trastuzumab + AI +/- Chemotherapy Arm B: Trastuzumab + AI +/- Chemotherapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    120 / 127 (94.49%)
    116 / 124 (93.55%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    9 / 127 (7.09%)
    9 / 124 (7.26%)
         occurrences all number
    14
    17
    Hypertension
         subjects affected / exposed
    22 / 127 (17.32%)
    24 / 124 (19.35%)
         occurrences all number
    54
    65
    Lymphoedema
         subjects affected / exposed
    7 / 127 (5.51%)
    5 / 124 (4.03%)
         occurrences all number
    10
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    39 / 127 (30.71%)
    32 / 124 (25.81%)
         occurrences all number
    76
    77
    Chest pain
         subjects affected / exposed
    9 / 127 (7.09%)
    9 / 124 (7.26%)
         occurrences all number
    11
    11
    Chills
         subjects affected / exposed
    8 / 127 (6.30%)
    7 / 124 (5.65%)
         occurrences all number
    8
    8
    Fatigue
         subjects affected / exposed
    21 / 127 (16.54%)
    25 / 124 (20.16%)
         occurrences all number
    33
    43
    Influenza like illness
         subjects affected / exposed
    10 / 127 (7.87%)
    7 / 124 (5.65%)
         occurrences all number
    17
    10
    Mucosal inflammation
         subjects affected / exposed
    14 / 127 (11.02%)
    13 / 124 (10.48%)
         occurrences all number
    20
    15
    Oedema peripheral
         subjects affected / exposed
    34 / 127 (26.77%)
    23 / 124 (18.55%)
         occurrences all number
    53
    34
    Pyrexia
         subjects affected / exposed
    17 / 127 (13.39%)
    13 / 124 (10.48%)
         occurrences all number
    22
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    25 / 127 (19.69%)
    18 / 124 (14.52%)
         occurrences all number
    36
    27
    Dyspnoea
         subjects affected / exposed
    20 / 127 (15.75%)
    13 / 124 (10.48%)
         occurrences all number
    22
    17
    Epistaxis
         subjects affected / exposed
    14 / 127 (11.02%)
    13 / 124 (10.48%)
         occurrences all number
    18
    20
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    14 / 127 (11.02%)
    5 / 124 (4.03%)
         occurrences all number
    15
    6
    Depression
         subjects affected / exposed
    13 / 127 (10.24%)
    5 / 124 (4.03%)
         occurrences all number
    14
    6
    Insomnia
         subjects affected / exposed
    15 / 127 (11.81%)
    18 / 124 (14.52%)
         occurrences all number
    18
    23
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    13 / 127 (10.24%)
    8 / 124 (6.45%)
         occurrences all number
    19
    9
    Weight decreased
         subjects affected / exposed
    14 / 127 (11.02%)
    11 / 124 (8.87%)
         occurrences all number
    16
    12
    Weight increased
         subjects affected / exposed
    11 / 127 (8.66%)
    5 / 124 (4.03%)
         occurrences all number
    13
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    21 / 127 (16.54%)
    12 / 124 (9.68%)
         occurrences all number
    32
    12
    Headache
         subjects affected / exposed
    22 / 127 (17.32%)
    14 / 124 (11.29%)
         occurrences all number
    33
    24
    Neuropathy peripheral
         subjects affected / exposed
    18 / 127 (14.17%)
    17 / 124 (13.71%)
         occurrences all number
    26
    19
    Paraesthesia
         subjects affected / exposed
    13 / 127 (10.24%)
    11 / 124 (8.87%)
         occurrences all number
    19
    13
    Peripheral sensory neropathy
         subjects affected / exposed
    10 / 127 (7.87%)
    9 / 124 (7.26%)
         occurrences all number
    12
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    28 / 127 (22.05%)
    18 / 124 (14.52%)
         occurrences all number
    53
    30
    Neutropenia
         subjects affected / exposed
    11 / 127 (8.66%)
    13 / 124 (10.48%)
         occurrences all number
    14
    23
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    9 / 127 (7.09%)
    7 / 124 (5.65%)
         occurrences all number
    9
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 127 (7.87%)
    16 / 124 (12.90%)
         occurrences all number
    11
    18
    Abdominal pain upper
         subjects affected / exposed
    12 / 127 (9.45%)
    6 / 124 (4.84%)
         occurrences all number
    17
    6
    Constipation
         subjects affected / exposed
    18 / 127 (14.17%)
    19 / 124 (15.32%)
         occurrences all number
    27
    25
    Diarrhoea
         subjects affected / exposed
    70 / 127 (55.12%)
    45 / 124 (36.29%)
         occurrences all number
    213
    88
    Dyspepsia
         subjects affected / exposed
    8 / 127 (6.30%)
    9 / 124 (7.26%)
         occurrences all number
    9
    11
    Nausea
         subjects affected / exposed
    47 / 127 (37.01%)
    34 / 124 (27.42%)
         occurrences all number
    68
    56
    Stomatitis
         subjects affected / exposed
    17 / 127 (13.39%)
    11 / 124 (8.87%)
         occurrences all number
    24
    22
    Vomiting
         subjects affected / exposed
    31 / 127 (24.41%)
    21 / 124 (16.94%)
         occurrences all number
    42
    33
    Haemorrhoids
         subjects affected / exposed
    7 / 127 (5.51%)
    2 / 124 (1.61%)
         occurrences all number
    7
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    38 / 127 (29.92%)
    40 / 124 (32.26%)
         occurrences all number
    40
    50
    Dry skin
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 124 (4.84%)
         occurrences all number
    10
    7
    Nail disorder
         subjects affected / exposed
    9 / 127 (7.09%)
    5 / 124 (4.03%)
         occurrences all number
    13
    7
    Pruritus
         subjects affected / exposed
    20 / 127 (15.75%)
    14 / 124 (11.29%)
         occurrences all number
    42
    19
    Rash
         subjects affected / exposed
    23 / 127 (18.11%)
    12 / 124 (9.68%)
         occurrences all number
    35
    17
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    9 / 127 (7.09%)
    2 / 124 (1.61%)
         occurrences all number
    14
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    38 / 127 (29.92%)
    31 / 124 (25.00%)
         occurrences all number
    60
    49
    Back pain
         subjects affected / exposed
    23 / 127 (18.11%)
    21 / 124 (16.94%)
         occurrences all number
    29
    27
    Bone pain
         subjects affected / exposed
    16 / 127 (12.60%)
    10 / 124 (8.06%)
         occurrences all number
    25
    12
    Muscle spasms
         subjects affected / exposed
    14 / 127 (11.02%)
    5 / 124 (4.03%)
         occurrences all number
    17
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    11 / 127 (8.66%)
    4 / 124 (3.23%)
         occurrences all number
    13
    6
    Musculoskeletal pain
         subjects affected / exposed
    11 / 127 (8.66%)
    6 / 124 (4.84%)
         occurrences all number
    11
    8
    Myalgia
         subjects affected / exposed
    12 / 127 (9.45%)
    9 / 124 (7.26%)
         occurrences all number
    16
    9
    Pain in extremity
         subjects affected / exposed
    22 / 127 (17.32%)
    16 / 124 (12.90%)
         occurrences all number
    44
    23
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 127 (10.24%)
    7 / 124 (5.65%)
         occurrences all number
    21
    8
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 127 (10.24%)
    15 / 124 (12.10%)
         occurrences all number
    36
    23
    Urinary tract infection
         subjects affected / exposed
    17 / 127 (13.39%)
    16 / 124 (12.90%)
         occurrences all number
    25
    20
    Influenza
         subjects affected / exposed
    6 / 127 (4.72%)
    7 / 124 (5.65%)
         occurrences all number
    10
    12
    Paronychia
         subjects affected / exposed
    7 / 127 (5.51%)
    3 / 124 (2.42%)
         occurrences all number
    12
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 127 (18.11%)
    10 / 124 (8.06%)
         occurrences all number
    27
    14
    Hyperglycaemia
         subjects affected / exposed
    8 / 127 (6.30%)
    5 / 124 (4.03%)
         occurrences all number
    17
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Aug 2012
    1.The decision to include induction chemotherapy had to be made prior to randomization 2. The chemotherapy induction period was amended from “18 weeks” to “18 to 24 weeks” to allow for the application of different treatment schedules 3. Exclusion criteria were amended to exclude participants with CNS metastases only if they were not medically well controlled after receiving local therapy, to reduce the period since major surgery to randomization to 14 days, since receipt of intravenous antibiotics to 7 days, and to specify that use of chronic steroids referred to a period of ≥3 months and concurrent participation in a clinical study referred to therapeutic clinical studies 4. The sponsor would continue to provide pertuzumab for those participants who were still receiving the IMP at the end of the study and who are willing and considered suitable to enter an extension study for the purpose of collecting safety data and pre-specified efficacy measures 5. The dosing schedule of pertuzumab was amended (from Day 1 to Day 1 or Day 2) and an instruction was included to permit pertuzumab, trastuzumab and taxanes to be administered in any order (apart from Cycle 1) to allow more flexibility in the timing and order of administration of study medication 6. The interval duration for the scheduling of tumor assessments after 36 months was extended to reduce the burden of assessments for participants at this stage of the study 7. An IDMC was established to review safety
    28 Apr 2016
    1. Treatment of participants with initially inoperable locally advanced breast cancer at inclusion which subsequently became resectable was at the investigator’s discretion 2. The follow-up period for the evaluation of OS was extended from 24 months to 60 months 3. For this protocol, mortality was an efficacy endpoint. It was clarified that death should be considered an outcome and not a distinct event. An independent monitoring committee was to monitor the frequency of deaths from all causes 4. Participants with limited liver abnormalities were allowed in the study
    20 Sep 2016
    1. The definition for abnormal liver function test AEs reverted to the definition used for Version 2.0 of the protocol. This amendment was introduced following a request from the Medicines and Healthcare products Regulatory Agency in the United Kingdom (UK) and to ensure that there was consistency within the PERTAIN (EudraCT number 2011-002132-10) study assessments over time and globally 2. The Schedule of Assessments was revised to reflect the fact that an increased follow-up visit tolerance of an additional 5 weeks, 18 weeks in total, was now permitted for participants who were progression-free for >36 months

    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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