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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

    Results information
    Results version number
    		 v1
    This version publication date
    27 May 2017
    First version publication date
    27 May 2017
    Other versions
    		 v2

    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
    Interim
    Date of interim/final analysis
    17 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Mar 2016
    Global end of trial reached?
    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 from 17 February 2012. Results are presented here up to data cut-off date (17 March 2016).

    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)
    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)
    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) Arm B (Trastuzumab+AI)
    Started
    129
    129
    Completed
    80
    79
    Not completed
    49
    50
         Consent withdrawn by subject
    13
    13
         Death
    33
    28
         Reason not specified
    2
    3
         Lost to follow-up
    1
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A (Pertuzumab+Trastuzumab+AI)
    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)
    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) Arm B (Trastuzumab+AI) Total
    Number of subjects
    		 129 129
    Age categorical
    Units: Subjects
    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

    End points

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    End points reporting groups
    Reporting group title
    Arm A (Pertuzumab+Trastuzumab+AI)
    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)
    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
    PFS is 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). Progressive disease 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). In addition to the relative increase of 20%, the sum 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. Intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline to progressive disease or death (approximately, up to 49 months)
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    129
    129
    Units: months
        median (confidence interval 95%)
    18.89 (14.09 to 27.66)
    15.8 (11.04 to 18.56)
    Statistical analysis title
    		 PFS
    Statistical analysis description
    Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant therapy stratification factors from interactive response system (IXRS). Hazard ratio from stratified Cox proportional hazards model including stratification factors from interactive response system (IXRS).
    Comparison groups
    Arm A (Pertuzumab+Trastuzumab+AI) v Arm B (Trastuzumab+AI)
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    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

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomisation to the date of death, regardless of the cause of death. Subjects who were alive at the time of the analysis were censored at the date of the last follow-up assessment. Subjects without follow-up assessment were censored at the day of last study medication (pertuzumab, trastuzumab, AI or induction chemotherapy), and subjects with no post-baseline information were censored at the date of randomisation. ITT population included all randomised subjects. Here, 99999 indicates median, lower and upper limit of confidence limit (CI) for Arm A as it was not reached. 99999 indicates median and upper limit of CI for Arm B as it was not reached.
    End point type
    Secondary
    End point timeframe
    From the date of randomisation until first documented death (approximately, up to 49 months)
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    129
    129
    Units: months
        median (confidence interval 95%)
    99999 (-99999 to 99999)
    99999 (41.4 to 99999)
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    Stratified log-rank test based upon Kaplan-Meier including induction chemotherapy and prior adjuvant therapy stratification factors from IXRS.Hazard ratio from stratified Cox proportional hazards model including stratification factors from IXRS.
    Comparison groups
    Arm A (Pertuzumab+Trastuzumab+AI) v Arm B (Trastuzumab+AI)
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    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

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    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. Subjects 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. ITT population included all randomised subjects. Here, 99999 indicates upper limit of CI as it was not reached.
    End point type
    Secondary
    End point timeframe
    Baseline up to 49 months, approximately
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    69 [1]
    59 [2]
    Units: Percentage
        median (confidence interval 95%)
    27.1 (14.13 to 99999)
    15.11 (12.09 to 20.96)
    Notes
    [1] - Number of subjects analyzed: subjects who were responders and had measurable disease at baseline.
    [2] - Number of subjects analyzed: subjects who were responders and had measurable disease at baseline.
    Statistical analysis title
    		 DOR
    Statistical analysis description
    Median and log-rank test from unstratified analysis based upon Kaplan-Meier approach. 95% CI for medians are determined using the log-log transformation. Hazard ratio from stratified Cox proportional hazards model including stratification factors from IXRS.
    Comparison groups
    Arm A (Pertuzumab+Trastuzumab+AI) v Arm B (Trastuzumab+AI)
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0181
    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

    Secondary: Time to Response (TTR)

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    End point title
    		 Time to Response (TTR)
    End point description
    TTR was defined as the time from the date of randomisation to the date of first CR or 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. A censored time to response was calculated at the date of the last adequate tumor assessment as there was no date of confirmed response (CR or PR). 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 randomisation).
    End point type
    Secondary
    End point timeframe
    Baseline up to 49 months, approximately
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    109 [3]
    106 [4]
    Units: Months
        median (confidence interval 95%)
    2.53 (2.1 to 4.37)
    3.91 (2.1 to 4.17)
    Notes
    [3] - Here, number of subjects analyzed are the responders who had measurable disease at baseline.
    [4] - Here, number of subjects analyzed are the responders who had measurable disease at baseline.
    Statistical analysis title
    		 TTR
    Statistical analysis description
    Median and log-rank test from unstratified analysis based upon Kaplan-Meier approach. 95% CI for medians are determined using the log-log transformation. Hazard ratio from stratified Cox proportional hazards model including stratification factors from IXRS.
    Comparison groups
    Arm A (Pertuzumab+Trastuzumab+AI) v Arm B (Trastuzumab+AI)
    Number of subjects included in analysis
    215
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5597
    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

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as subjects with best (confirmed) overall response (BOR) of either CR or PR. ORR was assessed by the investigator according to RECIST version 1.1 and is based on BOR, which is defined as best response recorded from start of study treatment until disease progression/recurrence or death. 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; 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. Subjects needed to have two consecutive assessments of PR or CR to be a responder. Only subjects with measurable disease at baseline were included in the analysis of BOR and who did not have any evaluable post-baseline assessments were classified as not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline up to 49 months, approximately
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    109 [5]
    106 [6]
    Units: percentage of subjects
        number (confidence interval 95%)
    63.3 (53.5 to 72.3)
    55.7 (45.7 to 65.3)
    Notes
    [5] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    [6] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    No statistical analyses for this end point

    Secondary: Clinical Benefit Response (CBR)

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    End point title
    		 Clinical Benefit Response (CBR)
    End point description
    CBR is percentage of subjects with best (confirmed) PR or CR or 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; 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. ITT population included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to 49 months, approximately
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    109 [7]
    106 [8]
    Units: percentage of subjects
        number (confidence interval 95%)
    68.8 (59.2 to 77.3)
    67 (57.2 to 75.8)
    Notes
    [7] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    [8] - Here, number of subjects analyzed are the subjects who had measurable disease at baseline.
    No statistical analyses for this end point

    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
    EQ-5D VAS: subjectt 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. ITT population included all randomised subjects. Here, ‘n’ number of subjects who were evaluated at specified time point. Here, 99999 indicates standard deviation as it was not estimable because only 1 subject was evaluated for Cycle 57. 99999 indicates mean and standard deviation as no subject was evaluated at Cycle 60.
    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) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    129
    129
    Units: EQ-5D VAS
    arithmetic mean (standard deviation)
        Cycle 3 (n= 87, 87)
    3.3 ( 14.9 )
    1.9 ( 15.67 )
        Cycle 6 (n= 82, 75)
    3.5 ( 18.91 )
    0.5 ( 13.63 )
        Cycle 9 (n= 68, 66)
    5.3 ( 18.8 )
    2.1 ( 15.2 )
        Cycle 12 (n= 58, 52)
    10.7 ( 17.91 )
    4 ( 15.34 )
        Cycle 15 (n= 54, 50)
    9.1 ( 17.25 )
    1.4 ( 22.16 )
        Cycle 18 (n= 47, 43)
    7.5 ( 12.85 )
    3.5 ( 15.76 )
        Cycle 21 (n= 44, 39)
    5.8 ( 13.68 )
    3.5 ( 19.7 )
        Cycle 24 (n= 39, 38)
    6.2 ( 14.3 )
    3.2 ( 16.66 )
        Cycle 27 (n= 35, 33)
    7.5 ( 14.01 )
    2.6 ( 21.08 )
        Cycle 30 (n= 32, 28)
    8.4 ( 14.46 )
    3.3 ( 14.86 )
        Cycle 33 (n= 30, 23)
    4.8 ( 14.94 )
    3.6 ( 15.56 )
        Cycle 36 (n= 25, 20)
    5 ( 13.46 )
    5.3 ( 15.26 )
        Cycle 39 (n= 21, 14)
    6 ( 15.46 )
    10.4 ( 15.89 )
        Cycle 42 (n= 16, 11)
    3.4 ( 17.67 )
    11.4 ( 19.38 )
        Cycle 45 (n= 13, 8)
    8.5 ( 12.48 )
    9.3 ( 21.3 )
        Cycle 48 (n= 9, 4)
    3.3 ( 8.66 )
    -1.8 ( 2.36 )
        Cycle 51 (n= 6, 4)
    3.3 ( 11.69 )
    7 ( 12.36 )
        Cycle 54 (n= 3, 2)
    16.7 ( 17.56 )
    17.5 ( 17.68 )
        Cycle 57 (n= 2, 0)
    5 ( 7.07 )
    99999 ( 99999 )
        Cycle 60 (n= 1, 0)
    -5 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With any Adverse Event (AE)

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    End point title
    		 Percentage of Subjects With any Adverse Event (AE)
    End point description
    An AE was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study and laboratory or clinical tests that resulted in a change in treatment or discontinuation from study drug were reported as adverse events. Safety population included all subjects who had received at least 1 dose of any study medication assigned to treatment arms as treated.
    End point type
    Secondary
    End point timeframe
    Up to 49 months approximately
    End point values
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Number of subjects analysed
    127
    124
    Units: percentage of subjects
        number (not applicable)
    96.1
    98.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to cut-off date 17 March 2016 (approximate 49 months)
    Adverse event reporting additional description
    Safety population included all subjects who had received at least 1 dose of any study medication assigned to treatment arms as treated.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Arm A (Pertuzumab+Trastuzumab+AI)
    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)
    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) Arm B (Trastuzumab+AI)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 127 (33.07%)
    24 / 124 (19.35%)
         number of deaths (all causes)
    33
    28
         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
    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 / 0
    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
    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
    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
    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
    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
    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
    Investigations
    Ejection fraction decreased
         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
    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
    2 / 127 (1.57%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         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
    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
    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
    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
    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
    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
    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
    Vomiting
         subjects affected / exposed
    1 / 127 (0.79%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         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
    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
    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
    1 / 127 (0.79%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    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%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         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
    5 / 127 (3.94%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    1 / 6
    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
    Viral diarrhoea
         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
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A (Pertuzumab+Trastuzumab+AI) Arm B (Trastuzumab+AI)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 127 (93.70%)
    115 / 124 (92.74%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    8 / 127 (6.30%)
    9 / 124 (7.26%)
         occurrences all number
    12
    17
    Hypertension
         subjects affected / exposed
    19 / 127 (14.96%)
    23 / 124 (18.55%)
         occurrences all number
    42
    63
    Lymphoedema
         subjects affected / exposed
    7 / 127 (5.51%)
    4 / 124 (3.23%)
         occurrences all number
    9
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    39 / 127 (30.71%)
    31 / 124 (25.00%)
         occurrences all number
    69
    74
    Chest pain
         subjects affected / exposed
    9 / 127 (7.09%)
    7 / 124 (5.65%)
         occurrences all number
    11
    9
    Chills
         subjects affected / exposed
    8 / 127 (6.30%)
    7 / 124 (5.65%)
         occurrences all number
    8
    7
    Fatigue
         subjects affected / exposed
    21 / 127 (16.54%)
    24 / 124 (19.35%)
         occurrences all number
    32
    41
    Influenza like illness
         subjects affected / exposed
    9 / 127 (7.09%)
    6 / 124 (4.84%)
         occurrences all number
    15
    7
    Mucosal inflammation
         subjects affected / exposed
    14 / 127 (11.02%)
    11 / 124 (8.87%)
         occurrences all number
    20
    13
    Oedema peripheral
         subjects affected / exposed
    31 / 127 (24.41%)
    22 / 124 (17.74%)
         occurrences all number
    46
    32
    Pyrexia
         subjects affected / exposed
    15 / 127 (11.81%)
    11 / 124 (8.87%)
         occurrences all number
    20
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    22 / 127 (17.32%)
    17 / 124 (13.71%)
         occurrences all number
    27
    23
    Dyspnoea
         subjects affected / exposed
    18 / 127 (14.17%)
    12 / 124 (9.68%)
         occurrences all number
    19
    15
    Epistaxis
         subjects affected / exposed
    14 / 127 (11.02%)
    12 / 124 (9.68%)
         occurrences all number
    18
    15
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    12 / 127 (9.45%)
    5 / 124 (4.03%)
         occurrences all number
    12
    5
    Depression
         subjects affected / exposed
    9 / 127 (7.09%)
    6 / 124 (4.84%)
         occurrences all number
    9
    7
    Insomnia
         subjects affected / exposed
    13 / 127 (10.24%)
    17 / 124 (13.71%)
         occurrences all number
    14
    21
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    12 / 127 (9.45%)
    6 / 124 (4.84%)
         occurrences all number
    16
    7
    Weight decreased
         subjects affected / exposed
    13 / 127 (10.24%)
    10 / 124 (8.06%)
         occurrences all number
    15
    11
    Weight increased
         subjects affected / exposed
    9 / 127 (7.09%)
    5 / 124 (4.03%)
         occurrences all number
    11
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 127 (14.96%)
    11 / 124 (8.87%)
         occurrences all number
    26
    11
    Dysguesia
         subjects affected / exposed
    9 / 127 (7.09%)
    8 / 124 (6.45%)
         occurrences all number
    12
    10
    Headache
         subjects affected / exposed
    22 / 127 (17.32%)
    14 / 124 (11.29%)
         occurrences all number
    28
    24
    Neuropathy peripheral
         subjects affected / exposed
    17 / 127 (13.39%)
    17 / 124 (13.71%)
         occurrences all number
    22
    19
    Paraesthesia
         subjects affected / exposed
    13 / 127 (10.24%)
    11 / 124 (8.87%)
         occurrences all number
    18
    13
    Peripheral sensory neropathy
         subjects affected / exposed
    9 / 127 (7.09%)
    9 / 124 (7.26%)
         occurrences all number
    11
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 127 (20.47%)
    18 / 124 (14.52%)
         occurrences all number
    44
    30
    Neutropenia
         subjects affected / exposed
    11 / 127 (8.66%)
    12 / 124 (9.68%)
         occurrences all number
    14
    22
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    8 / 127 (6.30%)
    7 / 124 (5.65%)
         occurrences all number
    8
    8
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 127 (7.87%)
    12 / 124 (9.68%)
         occurrences all number
    11
    14
    Abdominal pain upper
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 124 (4.84%)
         occurrences all number
    11
    6
    Constipation
         subjects affected / exposed
    16 / 127 (12.60%)
    19 / 124 (15.32%)
         occurrences all number
    24
    25
    Diarrhoea
         subjects affected / exposed
    70 / 127 (55.12%)
    44 / 124 (35.48%)
         occurrences all number
    200
    84
    Dyspepsia
         subjects affected / exposed
    8 / 127 (6.30%)
    8 / 124 (6.45%)
         occurrences all number
    9
    9
    Nausea
         subjects affected / exposed
    41 / 127 (32.28%)
    32 / 124 (25.81%)
         occurrences all number
    59
    53
    Stomatitis
         subjects affected / exposed
    17 / 127 (13.39%)
    11 / 124 (8.87%)
         occurrences all number
    23
    21
    Vomiting
         subjects affected / exposed
    29 / 127 (22.83%)
    21 / 124 (16.94%)
         occurrences all number
    39
    31
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    36 / 127 (28.35%)
    40 / 124 (32.26%)
         occurrences all number
    38
    49
    Dry skin
         subjects affected / exposed
    7 / 127 (5.51%)
    6 / 124 (4.84%)
         occurrences all number
    9
    7
    Nail disorder
         subjects affected / exposed
    9 / 127 (7.09%)
    4 / 124 (3.23%)
         occurrences all number
    13
    6
    Pruritus
         subjects affected / exposed
    18 / 127 (14.17%)
    12 / 124 (9.68%)
         occurrences all number
    32
    15
    Rash
         subjects affected / exposed
    22 / 127 (17.32%)
    11 / 124 (8.87%)
         occurrences all number
    32
    17
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    9 / 127 (7.09%)
    1 / 124 (0.81%)
         occurrences all number
    13
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    37 / 127 (29.13%)
    29 / 124 (23.39%)
         occurrences all number
    49
    42
    Back pain
         subjects affected / exposed
    20 / 127 (15.75%)
    20 / 124 (16.13%)
         occurrences all number
    21
    26
    Bone pain
         subjects affected / exposed
    16 / 127 (12.60%)
    9 / 124 (7.26%)
         occurrences all number
    25
    11
    Muscle spasms
         subjects affected / exposed
    12 / 127 (9.45%)
    5 / 124 (4.03%)
         occurrences all number
    13
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    9 / 127 (7.09%)
    4 / 124 (3.23%)
         occurrences all number
    9
    5
    Musculoskeletal pain
         subjects affected / exposed
    8 / 127 (6.30%)
    6 / 124 (4.84%)
         occurrences all number
    8
    8
    Myalgia
         subjects affected / exposed
    11 / 127 (8.66%)
    9 / 124 (7.26%)
         occurrences all number
    12
    9
    Pain in extremity
         subjects affected / exposed
    21 / 127 (16.54%)
    15 / 124 (12.10%)
         occurrences all number
    30
    22
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 127 (8.66%)
    6 / 124 (4.84%)
         occurrences all number
    20
    7
    Upper respiratory tract infection NOS
         subjects affected / exposed
    12 / 127 (9.45%)
    13 / 124 (10.48%)
         occurrences all number
    20
    17
    Urinary tract infection
         subjects affected / exposed
    16 / 127 (12.60%)
    14 / 124 (11.29%)
         occurrences all number
    20
    17
    Influenza
         subjects affected / exposed
    4 / 127 (3.15%)
    7 / 124 (5.65%)
         occurrences all number
    4
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    20 / 127 (15.75%)
    10 / 124 (8.06%)
         occurrences all number
    21
    13

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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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