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    Clinical Trial Results:
    A Two-cohort, Open-label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in First Line Patients With HER2-positive Advanced (Metastatic or Locally Advanced) Breast Cancer

    Summary
    EudraCT number
    		 2011-003308-18
    Trial protocol
    		 ES   IT   DE   DK  
    Global end of trial date
    15 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Oct 2016
    First version publication date
    16 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MO27782
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01565083
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 61 6878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this 2-cohort, open-label, multicenter, phase 2 study was overall response rates (ORR), assessed by investigator, of pertuzumab given in combination with trastuzumab (Herceptin) and vinorelbine in first line participants with metastatic or locally advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Participants received pertuzumab and trastuzumab administered sequentially as separate intravenous (IV) infusions (followed by vinorelbine) and conventional sequential administration of pertuzumab and trastuzumab in separate infusion bags, followed by vinorelbine.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP). Approval from the Independent Ethics Committee/Institutional Review Board (IEC/IRB) was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval. The Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 32
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Italy: 37
    Worldwide total number of subjects
    213
    EEA total number of subjects
    154
    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)
    154
    From 65 to 84 years
    58
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Due to non-randomized nature of the study (single infusion cohort started enrollment only after separate infusion cohort recruitment was completed) and different baseline characteristics of participants, the comparison between the 2 cohorts was not performed. Hence, the efficacy and safety results for the 2 cohorts should be considered separately.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion
    Arm description
    		 Pertuzumab IV infusion at a loading dose of 840 milligrams (mg) on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg per kilogram (mg/kg) on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg per meter-squared (mg/m^2) on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
    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
    Loading dose of 840 mg on Day 1 of first 21-day cycle, followed by 420 mg on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Loading dose of 8 mg/kg on Day 1 of first 21-day cycle, followed by 6 mg/kg on Day 1 or 2 of each subsequent cycle.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 25 mg/m^2 followed by 30-35 mg/m^2 on Days 2 and 9 of the first 21-day cycle and on Days 1 and 8 (or Days 2 and 9) of each subsequent cycle.

    Arm title
    		 Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Arm description
    		 Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).
    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
    Loading dose of 840 mg on Day 1 of first 21-day cycle, followed by 420 mg on Day 1 of each subsequent cycle.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Loading dose of 8 mg/kg on Day 1 of first 21-day cycle, followed by 6 mg/kg on Day 1 or 2 of each subsequent cycle.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 25 mg/m^2 followed by 30-35 mg/m^2 on Days 2 and 9 of the first 21-day cycle and on Days 1 and 8 (or Days 2 and 9) of each subsequent cycle.

    Number of subjects in period 1
    		Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Started
    106
    107
    Completed
    73
    68
    Not completed
    33
    39
         Consent withdrawn by subject
    6
    4
         Death
    22
    23
         Unspecified
    3
    5
         Lost to follow-up
    2
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 milligrams (mg) on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg per kilogram (mg/kg) on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg per meter-squared (mg/m^2) on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Reporting group values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion Total
    Number of subjects
    		 106 107 213
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.9 ( 11.8 ) 55.6 ( 13.17 ) -
    Gender categorical
    Units: Subjects
        Female
    		 106 106 212
        Male
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 milligrams (mg) on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg per kilogram (mg/kg) on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg per meter-squared (mg/m^2) on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population included all participants enrolled into the study was used for all analyses in this study.

    Primary: Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

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    End point title
    		 Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [1]
    End point description
    Tumor response was assessed by investigator according to RECIST v1.1. BOR was defined as percentage of participants with a confirmed complete response (CR) or partial response (PR). All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total or pathological nodes (with short axis [SA] of at least (>/=) 15 millimeter [mm]) were identified as target lesions (TLs) and measured and recorded at baseline. A sum of diameters (longest for non-nodal lesions, SA for nodal lesions) for all TLs was calculated and reported as baseline sum of diameters (SD). All other lesions (or sites of disease) were identified as non-TLs. CR: disappearance of all TLs and SA reduction to less than (<) 10 mm for nodal TLs/ non-TLs. PR: >/=30 percent (%) decrease in SD of TLs, taking as reference baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. The 95% confidence interval (CI) was computed using Clopper-Pearson approach. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Results were reported descriptively and were not planned to be analyzed for statistically significant differences between groups.
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    89 [2]
    91 [3]
    Units: percentage of participants
        number (confidence interval 95%)
    74.2 (63.8 to 82.9)
    63.7 (53 to 73.6)
    Notes
    [2] - Only participants with measurable disease at baseline were included in the analysis.
    [3] - Only participants with measurable disease at baseline were included in the analysis.
    No statistical analyses for this end point

    Secondary: Time to Response as Assessed by Investigator According to RECIST v 1.1

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    End point title
    		 Time to Response as Assessed by Investigator According to RECIST v 1.1
    End point description
    For participants with a BOR of CR or PR, time to response = (Date of first confirmed CR/PR - Date of first study treatment) + 1. For participants without a CR or PR, time to response = (Date of adequate last tumor assessment - Date of first study treatment) + 1. For participant with no tumor assessment (or if all assessments were progressive disease [PD]) the censoring day was set to date of first study treatment +1. CR: the disappearance of all TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR: >/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    89 [4]
    91 [5]
    Units: months
        median (confidence interval 95%)
    2.1 (2 to 2.2)
    2.2 (2.1 to 4.4)
    Notes
    [4] - Only participants with measurable disease at baseline were included in the analysis.
    [5] - Only participants with measurable disease at baseline were included in the analysis.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1

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    End point title
    		 Duration of Response (DOR) as Assessed by Investigator According to RECIST v 1.1
    End point description
    DOR in participants with a BOR of CR or PR, was defined as the period from date of initial PR or CR until date of PD or death from any cause. Participants with no documented PD or death after CR or PR were censored at last date at which they were known to have had the CR or PR, respectively (regardless of the response at intermediate assessments). CR: disappearance of all TLs and SA reduction to <10 mm for nodal TLs/ non-TLs. PR: >/=30% decrease in SD of TLs, taking as reference the baseline SD. Confirmation of response at 2 consecutive tumor assessments >/=4 weeks apart was required. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. The 95% CI was computed using log-log transformation. ITT population. Only participants with a BOR of CR or PR and with measurable disease at baseline were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    66
    58
    Units: months
        median (confidence interval 95%)
    13.3 (10.6 to 16.2)
    11.8 (7.5 to 17.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From any Cause

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    End point title
    		 Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1 or Death From any Cause
    End point description
    PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause was reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: percentage of participants
        number (not applicable)
    69.8
    67.3
    No statistical analyses for this end point

    Secondary: Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1

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    End point title
    		 Progression-free Survival (PFS) as Assessed by Investigator According to RECIST v 1.1
    End point description
    PFS was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or death due to any cause, whichever occurred first. Participants with no PFS events were censored at the time of the last evaluable tumor assessment. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 or died due to any cause were considered as having an event. The median PFS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: months
        median (confidence interval 95%)
    14.3 (11.2 to 17.5)
    11.5 (10.3 to 15.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1

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    End point title
    		 Percentage of Participants With Disease Progression as Assessed by Investigator According to RECIST v1.1
    End point description
    PD was defined as >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Percentage of participants with radio-graphically documented PD as assessed by investigator according to RECIST v1.1 was reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: percentage of participants
        number (not applicable)
    67.9
    61.7
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1

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    End point title
    		 Time to Progression (TTP) as Assessed by Investigator According to RECIST v 1.1
    End point description
    TTP was defined as the time from first intake of any study medication until the first radio-graphically documented PD as assessed by investigator according to RECIST v1.1. Participants who did not have a radio-graphically documented PD and had died due to reason other than PD were censored on the last available tumor assessment prior to the death date. Participants with no baseline or no tumor assessment after the baseline visit were censored on the date of first study treatment. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SD of TLs, taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions. Participants who had radio-graphically documented PD as assessed by investigator according to RECIST v1.1 were considered as having an event. The median TTP was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: months
        median (confidence interval 95%)
    14.9 (11.3 to 17.9)
    12.8 (10.4 to 17.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Died From any Cause

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    End point title
    		 Percentage of Participants Who Died From any Cause
    End point description
    Percentage of participants who died due to any cause was reported. ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline until death (up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: percentage of participants
        number (not applicable)
    21.7
    21.5
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from first intake of any study medication to the date of death, regardless of the cause of death. Participants who were known to be 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 treatment, and participants with no post-baseline information were censored at the date of first study treatment plus 1 day. Participants who died due to any cause were considered as having an event. The median OS was estimated using Kaplan-Meier method. The 95% CI was computed using log-log transformation. ITT population. The data ‘99999 (99999 to 99999)’ in the results signifies that median and corresponding CI could not be calculated due to low number of participants who had an event.
    End point type
    Secondary
    End point timeframe
    Baseline until death (up to approximately 3.5 years)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    106
    107
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score

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    End point title
    		 Change from Baseline in European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Visual Analogue Scale (VAS) Score
    End point description
    EQ-5D VAS: 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. ITT population. Here, 'Number of subjects analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point. The data ‘99999’ in the results signifies that either mean was not available because no participant was evaluable at indicated time points or standard deviation was not available because only 1 participant was evaluable at indicated time points.
    End point type
    Secondary
    End point timeframe
    Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    102
    102
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 102, 102)
    69.7 ( 22.74 )
    68.6 ( 23.58 )
        Change at Cycle 3 (n = 83, 90)
    0.9 ( 19.31 )
    1.7 ( 23.16 )
        Change at Cycle 6 (n= 68, 82)
    1 ( 23.59 )
    4.3 ( 24.49 )
        Change at Cycle 9 (n= 67, 68)
    2.2 ( 23 )
    6.6 ( 26.29 )
        Change at Cycle 12 (n= 53, 59)
    -1.4 ( 30.19 )
    6.8 ( 23.59 )
        Change at Cycle 15 (n= 43, 43)
    6.3 ( 19.34 )
    8.1 ( 24.45 )
        Change at Cycle 18 (n=32, 28)
    5.7 ( 21.83 )
    6.5 ( 22.12 )
        Change at Cycle 21 (n= 30, 27)
    3.2 ( 20 )
    1.3 ( 28.5 )
        Change at Cycle 24 (n= 25, 26)
    3.1 ( 17.06 )
    2.8 ( 23.16 )
        Change at Cycle 27 (n= 21, 24)
    5.9 ( 18.79 )
    1.1 ( 20.16 )
        Change at Cycle 30 (n= 18, 19)
    5.4 ( 19.87 )
    9.5 ( 19.68 )
        Change at Cycle 33 (n= 15, 15)
    2.9 ( 24.03 )
    13.4 ( 19.65 )
        Change at Cycle 36 (n=14, 7)
    4.8 ( 17.37 )
    7.3 ( 21.72 )
        Change at Cycle 39 (n=6, 1)
    15.8 ( 19.85 )
    50 ( 99999 )
        Change at Cycle 42 (n= 2, 0)
    -5 ( 14.14 )
    99999 ( 99999 )
        Change at Cycle 45 (n= 1, 0)
    5 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score

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    End point title
    		 Change from Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire Score
    End point description
    FACT-B questionnaire is used for assessment of health-related QoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: physical (7 items), functional (7 items), social/family (7 items); all 3 ranged from 0 to 28, emotional (6 items) ranging from 0 to 24, and breast cancer subscale (9 items) ranging from 0 to 36; high subscale score represents a better QoL. All single-item measures ranges from 0=‘Not at all’ to 4=‘Very much’. Total possible score ranged from 0 to 144. High scale score represents a better QoL. ITT population. Here, 'Number of subjects analysed' signifies the number of participants evaluable for this outcome measure and 'n' signifies the number of participants evaluable at specified time point. The data ‘99999’ in the results signifies that either mean was not available because no participant was evaluable or standard deviation was not available because only 1 participant was evaluable at indicated time points.
    End point type
    Secondary
    End point timeframe
    Baseline, thereafter every 3 cycles from Cycle 3 to Cycle 45 (each cycle = 21 days)
    End point values
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Number of subjects analysed
    100
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 100, 100)
    76.7 ( 13.46 )
    78.5 ( 16.06 )
        Change at Cycle 3 (n = 82, 90)
    -1.96 ( 10.872 )
    -2.57 ( 13.159 )
        Change at Cycle 6 (n= 70, 79)
    -0.97 ( 12.749 )
    0.47 ( 13.724 )
        Change at Cycle 9 (n= 65, 60)
    1.44 ( 13.189 )
    -0.42 ( 14.602 )
        Change at Cycle 12 (n= 52, 51)
    0.4 ( 12.057 )
    0.51 ( 14.51 )
        Change at Cycle 15 (n= 43, 44)
    2.72 ( 10.989 )
    0.09 ( 13.713 )
        Change at Cycle 18 (n= 32, 32)
    4.58 ( 11.801 )
    0.51 ( 16.512 )
        Change at Cycle 21 (n= 29, 24)
    3.22 ( 13.178 )
    -0.23 ( 16.116 )
        Change at Cycle 24 (n= 26, 23)
    1.19 ( 10.66 )
    -1.03 ( 14.546 )
        Change at Cycle 27 (n= 20, 22)
    4.91 ( 9.9 )
    0.55 ( 14.185 )
        Change at Cycle 30 (n= 18, 24)
    3.96 ( 11.082 )
    -0.26 ( 17.381 )
        Change at Cycle 33 (n= 14, 17)
    5.75 ( 13.272 )
    1.76 ( 19.179 )
        Change at Cycle 36 (n= 15, 13)
    1.26 ( 9.21 )
    2.74 ( 14.354 )
        Change at Cycle 39 (n= 6, 6)
    -3.68 ( 16.866 )
    7.33 ( 20.992 )
        Change at Cycle 42 (n= 4, 0)
    -0.17 ( 10.599 )
    99999 ( 99999 )
        Change at Cycle 45 (n= 1, 0)
    1 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 until 28 days after last study treatment (up to approximately 3.5 years)
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) are adverse events occurring between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pre-treatment state. Safety Population included all participants who received at least one dose of any study treatment in any of the 2 cohorts.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 2 of each subsequent cycle. Vinorelbine IV infusion (administered after trastuzumab) at a dose of 25 mg/m^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 2 and Day 9 of each subsequent cycle. Pertuzumab and trastuzumab were administered sequentially in separate infusion bags, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Reporting group title
    Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Reporting group description
    		 Pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (cycle length = 21 days), followed by 420 mg on Day 1 of each subsequent cycle. Trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 2 of Cycle 1, followed by 6 mg/kg on Day 1 of each subsequent cycle. Vinorelbine IV infusion at a dose of 25 mg/m^2 on Day 2 and Day 9 of Cycle 1, followed by 30-35 mg/m^2 on Day 1 and Day 8 of each subsequent cycle. If administration of all 3 drugs was well tolerated in Cycle 1, then on Day 1 of each subsequent cycle, pertuzumab 420 mg and trastuzumab 6 mg/kg was administered in a single infusion bag, followed by vinorelbine until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end (up to 47 cycles).

    Serious adverse events
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 106 (30.19%)
    44 / 107 (41.12%)
         number of deaths (all causes)
    23
    23
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastrointestinal stromal tumour
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         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
    Fatigue
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 107 (5.61%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    5 / 106 (4.72%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (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
    0 / 106 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         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
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Paraparesis
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensorimotor disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    6 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 106 (0.94%)
    3 / 107 (2.80%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia obstructive
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 106 (1.89%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 106 (0.94%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 107 (1.87%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         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 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 106 (0.94%)
    2 / 107 (1.87%)
         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 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nosocomial infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 106 (1.89%)
    4 / 107 (3.74%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    Sepsis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 106 (1.89%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 107 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 107 (0.93%)
         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
    		 Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 106 (97.17%)
    106 / 107 (99.07%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    7 / 106 (6.60%)
    5 / 107 (4.67%)
         occurrences all number
    8
    6
    Hypertension
         subjects affected / exposed
    8 / 106 (7.55%)
    31 / 107 (28.97%)
         occurrences all number
    11
    85
    Hypotension
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 107 (2.80%)
         occurrences all number
    9
    3
    Phlebitis
         subjects affected / exposed
    3 / 106 (2.83%)
    8 / 107 (7.48%)
         occurrences all number
    5
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    42 / 106 (39.62%)
    29 / 107 (27.10%)
         occurrences all number
    81
    48
    Chest pain
         subjects affected / exposed
    7 / 106 (6.60%)
    10 / 107 (9.35%)
         occurrences all number
    8
    12
    Chills
         subjects affected / exposed
    30 / 106 (28.30%)
    14 / 107 (13.08%)
         occurrences all number
    37
    16
    Extravasation
         subjects affected / exposed
    1 / 106 (0.94%)
    7 / 107 (6.54%)
         occurrences all number
    1
    7
    Fatigue
         subjects affected / exposed
    36 / 106 (33.96%)
    41 / 107 (38.32%)
         occurrences all number
    63
    73
    Influenza like illness
         subjects affected / exposed
    7 / 106 (6.60%)
    9 / 107 (8.41%)
         occurrences all number
    10
    10
    Mucosal inflammation
         subjects affected / exposed
    16 / 106 (15.09%)
    26 / 107 (24.30%)
         occurrences all number
    31
    33
    Oedema peripheral
         subjects affected / exposed
    6 / 106 (5.66%)
    13 / 107 (12.15%)
         occurrences all number
    8
    16
    Pain
         subjects affected / exposed
    7 / 106 (6.60%)
    12 / 107 (11.21%)
         occurrences all number
    10
    18
    Pyrexia
         subjects affected / exposed
    35 / 106 (33.02%)
    22 / 107 (20.56%)
         occurrences all number
    56
    28
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    6 / 106 (5.66%)
    4 / 107 (3.74%)
         occurrences all number
    7
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    18 / 106 (16.98%)
    24 / 107 (22.43%)
         occurrences all number
    24
    31
    Dyspnoea
         subjects affected / exposed
    12 / 106 (11.32%)
    26 / 107 (24.30%)
         occurrences all number
    15
    34
    Epistaxis
         subjects affected / exposed
    14 / 106 (13.21%)
    21 / 107 (19.63%)
         occurrences all number
    19
    25
    Nasal dryness
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 107 (5.61%)
         occurrences all number
    3
    7
    Nasal inflammation
         subjects affected / exposed
    3 / 106 (2.83%)
    8 / 107 (7.48%)
         occurrences all number
    3
    11
    Oropharyngeal pain
         subjects affected / exposed
    13 / 106 (12.26%)
    5 / 107 (4.67%)
         occurrences all number
    17
    6
    Rhinorrhoea
         subjects affected / exposed
    5 / 106 (4.72%)
    7 / 107 (6.54%)
         occurrences all number
    5
    9
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 106 (1.89%)
    10 / 107 (9.35%)
         occurrences all number
    2
    12
    Depression
         subjects affected / exposed
    10 / 106 (9.43%)
    8 / 107 (7.48%)
         occurrences all number
    11
    12
    Insomnia
         subjects affected / exposed
    10 / 106 (9.43%)
    19 / 107 (17.76%)
         occurrences all number
    10
    24
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 106 (7.55%)
    11 / 107 (10.28%)
         occurrences all number
    15
    18
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 106 (3.77%)
    10 / 107 (9.35%)
         occurrences all number
    5
    12
    Ejection fraction decreased
         subjects affected / exposed
    9 / 106 (8.49%)
    2 / 107 (1.87%)
         occurrences all number
    17
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    9 / 106 (8.49%)
    9 / 107 (8.41%)
         occurrences all number
    11
    13
    Weight decreased
         subjects affected / exposed
    22 / 106 (20.75%)
    22 / 107 (20.56%)
         occurrences all number
    23
    31
    Weight increased
         subjects affected / exposed
    1 / 106 (0.94%)
    6 / 107 (5.61%)
         occurrences all number
    1
    6
    Injury, poisoning and procedural complications
    Radiation skin injury
         subjects affected / exposed
    1 / 106 (0.94%)
    6 / 107 (5.61%)
         occurrences all number
    1
    8
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    3 / 106 (2.83%)
    7 / 107 (6.54%)
         occurrences all number
    3
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 106 (3.77%)
    16 / 107 (14.95%)
         occurrences all number
    4
    19
    Dysgeusia
         subjects affected / exposed
    9 / 106 (8.49%)
    8 / 107 (7.48%)
         occurrences all number
    9
    11
    Headache
         subjects affected / exposed
    15 / 106 (14.15%)
    27 / 107 (25.23%)
         occurrences all number
    18
    55
    Neuropathy peripheral
         subjects affected / exposed
    11 / 106 (10.38%)
    23 / 107 (21.50%)
         occurrences all number
    14
    33
    Paraesthesia
         subjects affected / exposed
    20 / 106 (18.87%)
    9 / 107 (8.41%)
         occurrences all number
    32
    18
    Peripheral sensory neuropathy
         subjects affected / exposed
    9 / 106 (8.49%)
    10 / 107 (9.35%)
         occurrences all number
    11
    12
    Polyneuropathy
         subjects affected / exposed
    5 / 106 (4.72%)
    8 / 107 (7.48%)
         occurrences all number
    7
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    36 / 106 (33.96%)
    19 / 107 (17.76%)
         occurrences all number
    87
    30
    Leukopenia
         subjects affected / exposed
    24 / 106 (22.64%)
    16 / 107 (14.95%)
         occurrences all number
    108
    62
    Neutropenia
         subjects affected / exposed
    54 / 106 (50.94%)
    61 / 107 (57.01%)
         occurrences all number
    183
    197
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 107 (5.61%)
         occurrences all number
    2
    8
    Lacrimation increased
         subjects affected / exposed
    6 / 106 (5.66%)
    6 / 107 (5.61%)
         occurrences all number
    6
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    15 / 106 (14.15%)
    19 / 107 (17.76%)
         occurrences all number
    21
    24
    Abdominal pain upper
         subjects affected / exposed
    20 / 106 (18.87%)
    22 / 107 (20.56%)
         occurrences all number
    23
    30
    Constipation
         subjects affected / exposed
    35 / 106 (33.02%)
    35 / 107 (32.71%)
         occurrences all number
    45
    47
    Diarrhoea
         subjects affected / exposed
    61 / 106 (57.55%)
    62 / 107 (57.94%)
         occurrences all number
    144
    179
    Dry mouth
         subjects affected / exposed
    2 / 106 (1.89%)
    7 / 107 (6.54%)
         occurrences all number
    2
    9
    Dyspepsia
         subjects affected / exposed
    7 / 106 (6.60%)
    15 / 107 (14.02%)
         occurrences all number
    9
    20
    Haemorrhoids
         subjects affected / exposed
    9 / 106 (8.49%)
    4 / 107 (3.74%)
         occurrences all number
    15
    4
    Nausea
         subjects affected / exposed
    52 / 106 (49.06%)
    44 / 107 (41.12%)
         occurrences all number
    98
    78
    Stomatitis
         subjects affected / exposed
    19 / 106 (17.92%)
    26 / 107 (24.30%)
         occurrences all number
    31
    37
    Vomiting
         subjects affected / exposed
    34 / 106 (32.08%)
    25 / 107 (23.36%)
         occurrences all number
    62
    32
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    27 / 106 (25.47%)
    28 / 107 (26.17%)
         occurrences all number
    31
    29
    Dry skin
         subjects affected / exposed
    7 / 106 (6.60%)
    12 / 107 (11.21%)
         occurrences all number
    7
    13
    Erythema
         subjects affected / exposed
    9 / 106 (8.49%)
    3 / 107 (2.80%)
         occurrences all number
    11
    3
    Nail disorder
         subjects affected / exposed
    6 / 106 (5.66%)
    6 / 107 (5.61%)
         occurrences all number
    6
    6
    Onychoclasis
         subjects affected / exposed
    2 / 106 (1.89%)
    8 / 107 (7.48%)
         occurrences all number
    2
    8
    Pruritus
         subjects affected / exposed
    12 / 106 (11.32%)
    9 / 107 (8.41%)
         occurrences all number
    13
    9
    Rash
         subjects affected / exposed
    25 / 106 (23.58%)
    12 / 107 (11.21%)
         occurrences all number
    38
    15
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 106 (2.83%)
    7 / 107 (6.54%)
         occurrences all number
    3
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    18 / 106 (16.98%)
    16 / 107 (14.95%)
         occurrences all number
    24
    22
    Back pain
         subjects affected / exposed
    18 / 106 (16.98%)
    27 / 107 (25.23%)
         occurrences all number
    24
    31
    Bone pain
         subjects affected / exposed
    13 / 106 (12.26%)
    7 / 107 (6.54%)
         occurrences all number
    14
    13
    Muscle spasms
         subjects affected / exposed
    21 / 106 (19.81%)
    28 / 107 (26.17%)
         occurrences all number
    25
    38
    Myalgia
         subjects affected / exposed
    20 / 106 (18.87%)
    11 / 107 (10.28%)
         occurrences all number
    26
    11
    Neck pain
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 107 (5.61%)
         occurrences all number
    2
    7
    Pain in extremity
         subjects affected / exposed
    14 / 106 (13.21%)
    29 / 107 (27.10%)
         occurrences all number
    19
    43
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    8 / 106 (7.55%)
    3 / 107 (2.80%)
         occurrences all number
    11
    3
    Cystitis
         subjects affected / exposed
    8 / 106 (7.55%)
    16 / 107 (14.95%)
         occurrences all number
    11
    22
    Gastroenteritis
         subjects affected / exposed
    6 / 106 (5.66%)
    3 / 107 (2.80%)
         occurrences all number
    7
    4
    Influenza
         subjects affected / exposed
    11 / 106 (10.38%)
    4 / 107 (3.74%)
         occurrences all number
    12
    5
    Nasopharyngitis
         subjects affected / exposed
    20 / 106 (18.87%)
    15 / 107 (14.02%)
         occurrences all number
    32
    29
    Paronychia
         subjects affected / exposed
    2 / 106 (1.89%)
    6 / 107 (5.61%)
         occurrences all number
    3
    12
    Rhinitis
         subjects affected / exposed
    14 / 106 (13.21%)
    7 / 107 (6.54%)
         occurrences all number
    16
    7
    Sinusitis
         subjects affected / exposed
    4 / 106 (3.77%)
    7 / 107 (6.54%)
         occurrences all number
    4
    10
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 106 (4.72%)
    15 / 107 (14.02%)
         occurrences all number
    6
    18
    Urinary tract infection
         subjects affected / exposed
    11 / 106 (10.38%)
    13 / 107 (12.15%)
         occurrences all number
    16
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    23 / 106 (21.70%)
    24 / 107 (22.43%)
         occurrences all number
    27
    27
    Hypocalcaemia
         subjects affected / exposed
    6 / 106 (5.66%)
    5 / 107 (4.67%)
         occurrences all number
    15
    5
    Hypokalaemia
         subjects affected / exposed
    7 / 106 (6.60%)
    5 / 107 (4.67%)
         occurrences all number
    10
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2012
    - As MO27782 was an open-label study, words referring to randomization were removed and/or replaced - The study treatment administration scheme was corrected - The algorithm for continuation and discontinuation of pertuzumab and trastuzumab based on left ventricular ejection fraction (LVEF) assessments were revised in order to be consistent with the baseline LVEF criteria of >/= 55% - Clarification of several exclusion criteria - Clarification of the role of the IDMC - Changes to the prior and concomitant medications and therapies - Change to the time of the final analysis of primary endpoint
    23 Jan 2013
    - Clarification of the timing of the IDMC review - Inclusion of participants who had received hormonal therapy. To reflect the current use of hormonal therapies and everolimus in the participant population, the protocol was amended to allow inclusion of participants who, prior to study entry had received up to two lines of hormonal therapies for metastatic or locally recurrent disease, one of which could have been in combination with everolimus - Inclusion of participants with central nervous system (CNS) metastases, if the CNS metastases were medically well controlled prior to screening (as assessed by the investigator) after receiving local therapy (irradiation, surgery, etc) but without anti-Human Epidermal Growth Factor Receptor (HER) 2 therapy - Clarification of several exclusion criteria (including the exclusion of participants with cardiac disorders at risk of an serious adverse event) - Endpoint assessment and study end. Modification to timing of final assessment of ORR to enable timely results, rather than an open-ended final assessment time. Clarification of OS analysis timing and end of study - Infusion times and scheduling. New instructions introduced to enable appropriate monitoring of safety during initial pertuzumab/trastuzumab infusions - Abnormal liver values. New section introduced providing guidance on abnormal liver values, as required by updated Roche protocol template - Clarification of coagulation testing and HER2 status assessments
    20 Jan 2014
    - Removal of the use of the Independent Review Committee to assess the primary endpoint. Amended to “the primary endpoint to include ORR as assessed by the Investigator” - Analysis sections updated to ensure an accurate description of data evaluation. Efficacy endpoints were to be presented by each cohort with an exploratory comparison between cohorts only - Pregnancy follow-up. Increased pregnancy follow-up, restrictions on breastfeeding and use of adequate contraception to 7 months following last dose of study medication, in line with changes to recommendations given in trastuzumab labeling - Scope of interim review. Defined to reflect that efficacy data were to have been provided if requested by the IDMC, as outlined in the IDMC charter - Definition of secondary variables (time to response, duration of response, PFS, time to progression and overall survival) were amended to be measured as time from first intake of study medication rather than time from date of enrollment as this provided a more accurate measure of these endpoints. Documentation of PFS was broadened to include the option of pathological diagnosis of progression

    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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