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    Clinical Trial Results:
    A Phase III trial to compare the safety and efficacy of lapatinib plus trastuzumab plus an aromatase inhibitor (AI) vs. trastuzumab plus an AI vs. lapatinib plus an AI as 1st- or 2nd- line therapy in postmenopausal subjects with hormone receptor+, HER2-positive metastatic breast cancer (MBC) who received prior trastuzumab and endocrine therapies

    Summary
    EudraCT number
    		 2010-019577-16
    Trial protocol
    		 DE   HU   IE   PL   BE   BG   NO   GB   LT   PT   ES   GR   IT  
    Global end of trial date
    06 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2023
    First version publication date
    05 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    114299
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01160211
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GlaxoSmithKline: EGF114299, Novartis: CLAP016A2307
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 42 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 42 613241111, Novartis.email@novartis.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
    06 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate superiority of Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) combination (treatment group A) vs. Trastuzumab + Aromatase Inhibitor (AI) combination (treatment group B) for Progression Free Survival (PFS).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 May 2011
    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
    Argentina: 27
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Bulgaria: 23
    Country: Number of subjects enrolled
    China: 13
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    India: 2
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Peru: 5
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Russian Federation: 46
    Country: Number of subjects enrolled
    Serbia: 13
    Country: Number of subjects enrolled
    Singapore: 3
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    369
    EEA total number of subjects
    90
    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)
    284
    From 65 to 84 years
    85
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study was conducted at 113 centers in 29 countries worldwide (Argentina, Australia, Belgium, Brazil, Bulgaria, China, Croatia, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Japan, Peru, Poland, Portugal, Republic of Korea, Russia, Serbia, Singapore, Spain, Taiwan, Turkey, UK, Ukraine and USA)

    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
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI)
    Arm description
    		 Lapatinib 1000 mg PO once daily + Trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1000 mg by mouth once a day

    Investigational medicinal product name
    Aromatase Inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator’s choice given by mouth once daily

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

    Arm title
    		 Lapatinib + Aromatase Inhibitor (AI)
    Arm description
    		 Lapatinib 1500 mg PO once daily + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aromatase Inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator’s choice given by mouth once daily

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1500 mg by mouth once a day

    Arm title
    		 Trastuzumab + Aromatase Inhibitor (AI)
    Arm description
    		 Trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Aromatase Inhibitor
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Aromatase inhibitor (either letrozole, anastrozole, or exemestane) of investigator’s choice given by mouth once daily

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Loading dose of 8 mg/kg IV followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks)

    Number of subjects in period 1
    		Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Started
    124
    123
    122
    Safety Set
    123
    123
    121
    Completed
    64
    64
    55
    Not completed
    60
    59
    67
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    4
    2
    2
         Data unavailable due to regulatory issues
    2
    -
    2
         Subject Reached Protocol-Defined Stopping Criteria
    49
    49
    59
         Lost to follow-up
    4
    8
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI)
    Reporting group description
    		 Lapatinib 1000 mg PO once daily + Trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Reporting group title
    Lapatinib + Aromatase Inhibitor (AI)
    Reporting group description
    		 Lapatinib 1500 mg PO once daily + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Reporting group title
    Trastuzumab + Aromatase Inhibitor (AI)
    Reporting group description
    		 Trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Reporting group values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI) Total
    Number of subjects
    		 124 123 122 369
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 92 92 100 284
        From 65-84 years
    		 32 31 22 85
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.9 ± 11.15 57.1 ± 9.98 54.9 ± 10.10 -
    Sex: Female, Male
    Units: Participants
        Female
    		 124 123 122 369
        Male
    		 0 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 1 3
        Asian
    		 31 31 32 94
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 3 4 3 10
        White
    		 89 85 84 258
        More than one race
    		 0 2 2 4
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI)
    Reporting group description
    		 Lapatinib 1000 mg PO once daily + Trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Reporting group title
    Lapatinib + Aromatase Inhibitor (AI)
    Reporting group description
    		 Lapatinib 1500 mg PO once daily + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Reporting group title
    Trastuzumab + Aromatase Inhibitor (AI)
    Reporting group description
    		 Trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV every 3 weeks (q3weeks) + an Aromatase Inhibitor (AI) of Investigator’s choice PO once daily.

    Primary: Median Kaplan Meier estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)

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    End point title
    		 Median Kaplan Meier estimates for PFS in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) [1] [2]
    End point description
    Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Disease progression was based on assessments by the Investigator.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 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: Only descriptive analysis performed
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint evaluated PFS comparing treatment group A (lapatinib+trastuzumab+AI) vs. treatment group B (trastuzumab+AI)
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    120
    117
    Units: Months
        median (confidence interval 95%)
    11.0 (8.3 to 13.8)
    5.6 (5.4 to 8.3)
    No statistical analyses for this end point

    Primary: Progression Free Survival (PFS) events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI)

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    End point title
    		 Progression Free Survival (PFS) events in Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) vs. Trastuzumab + Aromatase Inhibitor (AI) [3]
    End point description
    The Number of Participants with Progression free survival (PFS) events in the Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) arm vs. Trastuzumab + Aromatase Inhibitor (AI) arm was based on assessments by the Investigator.
    End point type
    Primary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 5 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary endpoint evaluated PFS comparing treatment group A (lapatinib+trastuzumab+AI) vs. treatment group B (trastuzumab+AI)
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    120
    117
    Units: Participants
        Disease progression or died (event)
    62
    75
        Censored, follow-up for disease progression ended
    7
    3
        Censored, f/p for disease progression ongoing
    51
    39
    Statistical analysis title
    		 PFS of lap.+trast.+AI vs. trast.+AI
    Statistical analysis description
    Null hypothesis H0: λ ≥ 1 or to reject it in favor of the alternative hypothesis HA: λ <1, where λ is the hazard ratio (HR) between Treatment Group A and Treatment Group B for progression-free survival.
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    237
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0063 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.88
    Notes
    [4] - Pike estimate of the treatment hazard ratio, <1 indicates a lower risk compared with trastuzumab + AI.

    Secondary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    Progression free survival (PFS) was defined as the interval of time between the date of randomization and the earliest date of disease progression (with radiological evidence) or death from any cause, or to the date of censor. Disease progression was based on assessments by the Investigator.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    124
    123
    122
    Units: Months
        median (confidence interval 95%)
    11.1 (10.0 to 15.3)
    8.3 (7.1 to 11.0)
    5.7 (5.5 to 8.3)
    Statistical analysis title
    		 PFS of lap.+trast.+AI vs. trast.+AI
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.79
    Statistical analysis title
    		 PFS of lap.+trast.+AI vs. lap.+AI
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Lapatinib + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.92
    Statistical analysis title
    		 PFS of lap.+AI vs. trast.+AI
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.15

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    Overall Response Rate (ORR) was defined as the proportion of participants achieving either a Complete Response (CR) or Partial Response (PR). The ORR was calculated from the Investigator’s assessment of response based on RECIST 1.1. Subjects with an unknown or missing response were treated as non-responders; i.e. they were included in the denominator when calculating the percentages. Subjects who do not have measurable disease contributed to the Response Rate based analyses, for the evaluation of CR, SD and PD.
    End point type
    Secondary
    End point timeframe
    Up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    124
    123
    122
    Units: Percentage of Participants
        number (confidence interval 95%)
    32.3 (24.2 to 41.2)
    22.8 (15.7 to 31.2)
    17.2 (11.0 to 25.1)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    The Number of Participants with Overall Survival (OS) events was based on assessments by the Investigator.
    End point type
    Secondary
    End point timeframe
    From date of randomization until date of death from any cause, assessed up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    124
    123
    122
    Units: Participants
        Death
    38
    45
    39
        Censored, follow-up ended
    86
    78
    83
        Censored, follow-up ongoing
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    Clinical Benefit Rate (CBR) was defined as the percentage of patients with evidence of Complete Response (CR), Partial Response (PR), or maintaining Stable Disease (SD) for at least 6 months while on study, according to the investigator assessment of response per RECIST 1.1 criteria.
    End point type
    Secondary
    End point timeframe
    Up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    124
    123
    122
    Units: Percentage of Participants
        number (confidence interval 95%)
    51.6 (42.5 to 60.7)
    43.1 (34.2 to 52.3)
    34.4 (26.1 to 43.6)
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to Response (TTR) was defined as the time from randomization to the earliest date of Complete Response (CR) or Partial Response (PR)
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of Complete Response (CR) or Partial Response (PR), assessed up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    40
    28
    21
    Units: Days
        median (full range (min-max))
    85.0 (72 to 1031)
    86.5 (65 to 1175)
    86.0 (67 to 337)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Duration of Response (DOR) was defined as the duration between the date of first documented Complete Response (CR) or Partial Response (PR) and the date of first documented sign of Progressive Disease or Death, or to the date of censor.
    End point type
    Secondary
    End point timeframe
    From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    40
    28
    21
    Units: Months
        median (confidence interval 95%)
    22.5 (11.1 to 33.1)
    11.1 (5.6 to 999)
    11.8 (5.4 to 28.1)
    No statistical analyses for this end point

    Secondary: Mean change in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On treatment Assessment

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    End point title
    		 Mean change in the Quality of Life (QoL) Status Relative to Baseline FACT-B Overall and Subscale Scores at Last On treatment Assessment
    End point description
    Quality of life was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. It is a 37-item (27 general questions and 10 breast cancer specific questions) self-reporting instrument consisting of 5 dimensions: physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The followings were the score ranges for each self-reporting subscale: • PWB : 0-28 • SWB : 0-28 • EWB : 0-24 • FWB : 0-28 • BCS : 0-40 FACT-B Total Outcome Index (TOI) = PWB + FWB + BCS (range:0 - 96) FACT-B Total Score = PWB + SWB + EWB + FWB + BCS (range:0-148) FACT-G Total Score = PWB + SWB + EWB + FWB (range:0-108). For all the FACIT scales and symptom indices, the higher the score the better QoL
    End point type
    Secondary
    End point timeframe
    Day 1 (pre-dose), up approximately 11 years
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    115
    113
    110
    Units: score on a scale
    least squares mean (standard error)
        FACT-B total score
    -4.2 ± 1.48
    -6.3 ± 1.51
    -2.4 ± 1.51
        FACT-G total score
    -4.3 ± 1.22
    -5.9 ± 1.24
    -2.8 ± 1.24
        FACT-B trial outcome Index (TOI)
    -3.3 ± 1.05
    -4.2 ± 1.07
    -0.6 ± 1.07
        Physical well-being (PWB)
    -2.0 ± 0.48
    -2.1 ± 0.49
    -0.5 ± 0.49
        Social family wellbeing (SWB)
    -0.5 ± 0.50
    -1.5 ± 0.50
    -0.9 ± 0.51
        Emotional wellbeing (EWB)
    -0.4 ± 0.40
    -0.6 ± 0.40
    -1.0 ± 0.41
        Functional wellbeing (FWB)
    -1.3 ± 0.45
    -1.7 ± 0.46
    -0.3 ± 0.46
        Breast cancer subscale (BCS)
    0.0 ± 0.47
    -0.5 ± 0.47
    0.4 ± 0.48
    Statistical analysis title
    		 FACT-B total score
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -1.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.95
         upper limit
    		 2.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.111
    Statistical analysis title
    		 FACT-B total score
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.09
         upper limit
    		 0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.13
    Statistical analysis title
    		 Emotional wellbeing (EWB)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 1.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.571
    Statistical analysis title
    		 Emotional wellbeing (EWB)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 1.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.568
    Statistical analysis title
    		 Social family wellbeing (SWB)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.96
         upper limit
    		 0.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.715
    Statistical analysis title
    		 FACT-G total score
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.92
         upper limit
    		 1.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.739
    Statistical analysis title
    		 FACT-G total score
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.55
         upper limit
    		 0.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.751
    Statistical analysis title
    		 FACT-B trial outcome index (TOI)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.66
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.502
    Statistical analysis title
    		 FACT-B trial outcome index (TOI)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.59
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.512
    Statistical analysis title
    		 Physical well-being (PWB)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -1.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.82
         upper limit
    		 -0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.69
    Statistical analysis title
    		 Physical well-being (PWB)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 -0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.693
    Statistical analysis title
    		 Social family wellbeing (SWB)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 1.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.711
    Statistical analysis title
    		 Functional wellbeing (FWB)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.649
    Statistical analysis title
    		 Functional wellbeing (FWB)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 0.28
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.646
    Statistical analysis title
    		 Breast cancer subscale (BCS)
    Comparison groups
    Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    225
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.665
    Statistical analysis title
    		 Breast cancer subscale (BCS)
    Comparison groups
    Lapatinib + Aromatase Inhibitor (AI) v Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Least square difference
    Point estimate
    -0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.668

    Post-hoc: All collected deaths

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    End point title
    		 All collected deaths
    End point description
    On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication, for a maximum duration of approximately 131 months. Post-treatment survival follow-up deaths were collected from day 31 after last dose of study medication to end of study, up to approximately 132 months. All deaths refer to the sum of on-treatment deaths and post-treatment survival follow-up deaths.
    End point type
    Post-hoc
    End point timeframe
    On-treatment deaths: Up to approximately 131 months. Post-treatment survival follow-up deaths: Up to approximately 132 months
    End point values
    		 Lapatinib + Trastuzumab + Aromatase Inhibitor (AI) Lapatinib + Aromatase Inhibitor (AI) Trastuzumab + Aromatase Inhibitor (AI)
    Number of subjects analysed
    123
    123
    121
    Units: Participants
        On-treatment deaths
    5
    8
    5
        Post-treatment survival follow-up deaths
    33
    37
    34
        All deaths
    38
    45
    39
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days, up to a maximum duration of approximately 131 months.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Lapatinib (1000mg) + Trastuzumab (6 mg/kg) + AI
    Reporting group description
    		 Lapatinib (1000mg) + Trastuzumab (6 mg/kg) + AI

    Reporting group title
    Trastuzumab (6 mg/kg) + AI
    Reporting group description
    		 Trastuzumab (6 mg/kg) + AI

    Reporting group title
    Lapatinib (1500mg) + AI
    Reporting group description
    		 Lapatinib (1500mg) + AI

    Serious adverse events
    		 Lapatinib (1000mg) + Trastuzumab (6 mg/kg) + AI Trastuzumab (6 mg/kg) + AI Lapatinib (1500mg) + AI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 123 (21.95%)
    14 / 121 (11.57%)
    23 / 123 (18.70%)
         number of deaths (all causes)
    5
    5
    8
         number of deaths resulting from adverse events
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Organ failure
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Iodine allergy
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    7 / 123 (5.69%)
    2 / 121 (1.65%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    6 / 8
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle strain
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural inflammation
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 123 (0.81%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pancreatitis acute
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelocaliectasis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 123 (2.44%)
    2 / 121 (1.65%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 123 (0.00%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyuria
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 123 (1.63%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 123 (0.00%)
    1 / 121 (0.83%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 123 (0.81%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 123 (1.63%)
    0 / 121 (0.00%)
    0 / 123 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lapatinib (1000mg) + Trastuzumab (6 mg/kg) + AI Trastuzumab (6 mg/kg) + AI Lapatinib (1500mg) + AI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 123 (91.87%)
    86 / 121 (71.07%)
    107 / 123 (86.99%)
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    10 / 123 (8.13%)
    3 / 121 (2.48%)
    3 / 123 (2.44%)
         occurrences all number
    10
    4
    3
    Blood bilirubin increased
         subjects affected / exposed
    3 / 123 (2.44%)
    1 / 121 (0.83%)
    8 / 123 (6.50%)
         occurrences all number
    3
    1
    8
    Blood alkaline phosphatase increased
         subjects affected / exposed
    5 / 123 (4.07%)
    9 / 121 (7.44%)
    7 / 123 (5.69%)
         occurrences all number
    5
    9
    8
    Aspartate aminotransferase increased
         subjects affected / exposed
    11 / 123 (8.94%)
    11 / 121 (9.09%)
    22 / 123 (17.89%)
         occurrences all number
    12
    12
    28
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 123 (8.94%)
    9 / 121 (7.44%)
    20 / 123 (16.26%)
         occurrences all number
    15
    11
    26
    Weight decreased
         subjects affected / exposed
    12 / 123 (9.76%)
    3 / 121 (2.48%)
    13 / 123 (10.57%)
         occurrences all number
    13
    3
    14
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 123 (7.32%)
    8 / 121 (6.61%)
    4 / 123 (3.25%)
         occurrences all number
    13
    9
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 123 (7.32%)
    15 / 121 (12.40%)
    21 / 123 (17.07%)
         occurrences all number
    13
    22
    25
    Dizziness
         subjects affected / exposed
    10 / 123 (8.13%)
    9 / 121 (7.44%)
    10 / 123 (8.13%)
         occurrences all number
    11
    9
    14
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    6 / 123 (4.88%)
    3 / 121 (2.48%)
    7 / 123 (5.69%)
         occurrences all number
    6
    7
    10
    Anaemia
         subjects affected / exposed
    8 / 123 (6.50%)
    8 / 121 (6.61%)
    7 / 123 (5.69%)
         occurrences all number
    11
    8
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 123 (12.20%)
    6 / 121 (4.96%)
    7 / 123 (5.69%)
         occurrences all number
    16
    36
    8
    Fatigue
         subjects affected / exposed
    15 / 123 (12.20%)
    12 / 121 (9.92%)
    19 / 123 (15.45%)
         occurrences all number
    17
    16
    20
    Oedema peripheral
         subjects affected / exposed
    8 / 123 (6.50%)
    5 / 121 (4.13%)
    5 / 123 (4.07%)
         occurrences all number
    8
    5
    5
    Pyrexia
         subjects affected / exposed
    7 / 123 (5.69%)
    6 / 121 (4.96%)
    6 / 123 (4.88%)
         occurrences all number
    11
    8
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    87 / 123 (70.73%)
    11 / 121 (9.09%)
    64 / 123 (52.03%)
         occurrences all number
    235
    11
    130
    Abdominal pain upper
         subjects affected / exposed
    9 / 123 (7.32%)
    9 / 121 (7.44%)
    7 / 123 (5.69%)
         occurrences all number
    9
    9
    8
    Dyspepsia
         subjects affected / exposed
    8 / 123 (6.50%)
    0 / 121 (0.00%)
    4 / 123 (3.25%)
         occurrences all number
    10
    0
    4
    Nausea
         subjects affected / exposed
    28 / 123 (22.76%)
    13 / 121 (10.74%)
    28 / 123 (22.76%)
         occurrences all number
    32
    17
    46
    Stomatitis
         subjects affected / exposed
    23 / 123 (18.70%)
    5 / 121 (4.13%)
    16 / 123 (13.01%)
         occurrences all number
    29
    5
    26
    Vomiting
         subjects affected / exposed
    16 / 123 (13.01%)
    1 / 121 (0.83%)
    19 / 123 (15.45%)
         occurrences all number
    17
    1
    28
    Cheilitis
         subjects affected / exposed
    7 / 123 (5.69%)
    0 / 121 (0.00%)
    1 / 123 (0.81%)
         occurrences all number
    8
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal dryness
         subjects affected / exposed
    7 / 123 (5.69%)
    1 / 121 (0.83%)
    3 / 123 (2.44%)
         occurrences all number
    8
    1
    3
    Epistaxis
         subjects affected / exposed
    10 / 123 (8.13%)
    0 / 121 (0.00%)
    8 / 123 (6.50%)
         occurrences all number
    11
    0
    10
    Dyspnoea
         subjects affected / exposed
    7 / 123 (5.69%)
    8 / 121 (6.61%)
    9 / 123 (7.32%)
         occurrences all number
    7
    8
    10
    Cough
         subjects affected / exposed
    12 / 123 (9.76%)
    17 / 121 (14.05%)
    16 / 123 (13.01%)
         occurrences all number
    14
    20
    18
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    14 / 123 (11.38%)
    2 / 121 (1.65%)
    8 / 123 (6.50%)
         occurrences all number
    14
    2
    8
    Rash maculo-papular
         subjects affected / exposed
    7 / 123 (5.69%)
    0 / 121 (0.00%)
    7 / 123 (5.69%)
         occurrences all number
    10
    0
    11
    Rash
         subjects affected / exposed
    43 / 123 (34.96%)
    3 / 121 (2.48%)
    36 / 123 (29.27%)
         occurrences all number
    64
    3
    51
    Pruritus
         subjects affected / exposed
    11 / 123 (8.94%)
    2 / 121 (1.65%)
    11 / 123 (8.94%)
         occurrences all number
    14
    2
    13
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    13 / 123 (10.57%)
    1 / 121 (0.83%)
    11 / 123 (8.94%)
         occurrences all number
    13
    1
    11
    Dry skin
         subjects affected / exposed
    11 / 123 (8.94%)
    0 / 121 (0.00%)
    11 / 123 (8.94%)
         occurrences all number
    12
    0
    11
    Dermatitis acneiform
         subjects affected / exposed
    16 / 123 (13.01%)
    2 / 121 (1.65%)
    11 / 123 (8.94%)
         occurrences all number
    25
    2
    15
    Skin fissures
         subjects affected / exposed
    7 / 123 (5.69%)
    2 / 121 (1.65%)
    3 / 123 (2.44%)
         occurrences all number
    8
    2
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 123 (4.07%)
    4 / 121 (3.31%)
    12 / 123 (9.76%)
         occurrences all number
    5
    4
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 123 (17.89%)
    15 / 121 (12.40%)
    19 / 123 (15.45%)
         occurrences all number
    29
    20
    23
    Back pain
         subjects affected / exposed
    9 / 123 (7.32%)
    10 / 121 (8.26%)
    12 / 123 (9.76%)
         occurrences all number
    10
    13
    13
    Bone pain
         subjects affected / exposed
    7 / 123 (5.69%)
    7 / 121 (5.79%)
    4 / 123 (3.25%)
         occurrences all number
    8
    8
    4
    Myalgia
         subjects affected / exposed
    7 / 123 (5.69%)
    8 / 121 (6.61%)
    6 / 123 (4.88%)
         occurrences all number
    7
    12
    7
    Pain in extremity
         subjects affected / exposed
    11 / 123 (8.94%)
    5 / 121 (4.13%)
    12 / 123 (9.76%)
         occurrences all number
    13
    6
    14
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 123 (5.69%)
    5 / 121 (4.13%)
    0 / 123 (0.00%)
         occurrences all number
    8
    5
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 123 (6.50%)
    10 / 121 (8.26%)
    6 / 123 (4.88%)
         occurrences all number
    10
    13
    7
    Paronychia
         subjects affected / exposed
    39 / 123 (31.71%)
    0 / 121 (0.00%)
    21 / 123 (17.07%)
         occurrences all number
    73
    0
    35
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 123 (10.57%)
    7 / 121 (5.79%)
    8 / 123 (6.50%)
         occurrences all number
    22
    8
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    22 / 123 (17.89%)
    4 / 121 (3.31%)
    18 / 123 (14.63%)
         occurrences all number
    25
    4
    20
    Hypokalaemia
         subjects affected / exposed
    9 / 123 (7.32%)
    0 / 121 (0.00%)
    8 / 123 (6.50%)
         occurrences all number
    16
    0
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2013
    Amendment 1: Country specific amendment for France. Protocol appendices 3 and 4 were updated to include the Diarrhea Management Guidelines and Dermatological Assessment Guidelines
    23 Jul 2013
    Amendment 2: Global amendment allowed entry of subjects who were receiving later lines of therapies, including at least one prior trastuzumab and chemotherapy regimen. Updates were made to inclusion/exclusion criteria; changes were made to prohibited medications (removal of restrictions around bisphosphonate use, allowance of denosumab, clarification on permitted use of radiotherapy, additions to prohibited medications table).
    29 Jan 2014
    Amendment 3: Country-specific amendment for France. Updates to protocol was done to include management guidelines for treatment of prolonged QT/QTc and a reference to a list of known drugs that cause QT/QTc prolongations were provided. Updates made to Dermatological Assessment Guidelines.
    10 Dec 2014
    Amendment 4: Country-specific amendment for China. Updates were done to protocol to adjust the time period of SAE collection in accordance with China regulations
    18 Mar 2016
    Amendment 5: Global amendment: Since study EGF114299 is a post-approval commitment to both the CHMP and the FDA, these regulatory agencies were consulted in light of the study enrollment challenges in this subject population (CHMP in October 2015 and FDA in September 2015). The primary endpoint was changed from OS to PFS. In addition, the amendment introduced the following changes: Secondary endpoints were updated, and survival follow-up removed The revised sample size was changed to approximately 345 subjects Country-specific amendments No. 3 and 4 for France and China, respectively, were included in this global amendment for harmonization purposes as it also applies to all countries Protocol appendices 3 and 4 were updated to include Diarrhea Management Guidelines and Dermatological Assessment Guidelines Protocol Section 5.8.4 and Section 6.2 were updated to include management guidelines for prolonged QT/QTc and to provide a reference to a list of drugs known to cause QT/QTc prolongations Protocol Section 7.3.3.5.was updated to adjust the time period of SAE collection in accordance with China regulations
    19 May 2016
    Amendment 6: Deleted or replaced references to GSK or its staff with that of Novartis and its authorized agents to align with the change of sponsorship; administrative changes to align with Novartis processes and procedures.

    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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