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    Clinical Trial Results:
    A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2-Directed Regimens in the Metastatic Setting (NALA)

    Summary
    EudraCT number
    		 2012-004492-38
    Trial protocol
    		 GB   DE   FI   IT   BE   CZ   ES   AT   SE   IE   DK   PT   NL  
    Global end of trial date
    09 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2020
    First version publication date
    13 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PUMA-NER-1301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01808573
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Puma Biotechnology, Inc.
    Sponsor organisation address
    10880 Wilshire Blvd, Suite 2150, Los Angeles, United States, 90024
    Public contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., +1 424248 6500, ClinicalTrials@PumaBiotechnology.com
    Scientific contact
    Clinical Trials Information Desk, Puma Biotechnology, Inc., +1 424248 6500, ClinicalTrials@PumaBiotechnology.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
    09 Dec 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The co-primary objectives of this study are to compare independently adjudicated progression free survival (PFS) following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive (HER2+) MBC who have received two or more prior HER2- directed regimens in the metastatic setting and compare overall survival (OS) following treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in this population.
    Protection of trial subjects
    Study commencement required prior written approval of a properly constituted Institutional Review Board (IRB) or Independent Ethics Committee (IEC). Clinical trial data were monitored at regular intervals by the Sponsor or their representative throughout the study to verify compliance to study protocol, completeness, accuracy and consistency of the data and adherence to local regulations on the conduct of clinical research. Patients were discontinued from investigational product(s) (IP) in the following circumstances: unacceptable toxicity, if patient required more than 2 dose reductions of neratinib, disease progression on combination therapy, initiation of alternative anti-cancer therapy, including chemotherapy, radiotherapy, and cancer-related surgery, pregnancy, or patient request.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2013
    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: 3
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Brazil: 35
    Country: Number of subjects enrolled
    Canada: 32
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Spain: 57
    Country: Number of subjects enrolled
    Finland: 10
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Hong Kong: 19
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Israel: 26
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Singapore: 22
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Taiwan: 110
    Country: Number of subjects enrolled
    United States: 92
    Worldwide total number of subjects
    621
    EEA total number of subjects
    195
    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)
    492
    From 65 to 84 years
    129
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment starting date is Mar 29, 2013.

    Pre-assignment
    Screening details
    		 Screening activities are to be conducted within 21 days prior to randomization. Baseline assessments must be done within 72 hours before randomization. Randomization should occur after all baseline assessments have been completed and the site confirms that the patient still meets all eligibility requirements.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Neratinib Plus Capecitabine
    Arm description
    		 Neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Neratinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Neratinib 240 mg orally, once daily with food.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 1500 mg/m^2, daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, 14 of each 21 day cycle.

    Arm title
    		 Lapatinib Plus Capecitabine
    Arm description
    		 Lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lapatinib 1250 mg orally, once daily, continuously in 21 day cycles.

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Number of subjects in period 1
    		Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Started
    307
    314
    Completed
    0
    0
    Not completed
    307
    314
         Randomized in error
    1
    -
         Consent withdrawn by subject
    12
    10
         Death
    212
    240
         Discontinuation of study by sponsor
    79
    64
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Neratinib Plus Capecitabine
    Reporting group description
    		 Neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Reporting group title
    Lapatinib Plus Capecitabine
    Reporting group description
    		 Lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Reporting group values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine Total
    Number of subjects
    		 307 314 621
    Age categorical
    Units: Subjects
        <65 years
    		 244 248 492
        >=65 years
    		 63 66 129
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.04 ± 11.37 54.32 ± 11.36 -
    Gender categorical
    Units: Subjects
        Female
    		 307 311 618
        Male
    		 0 3 3
    Previous HER2 Regimens
    Units: Subjects
        3 or more lines
    		 92 99 191
        2 lines
    		 215 215 430
    Disease Location
    Units: Subjects
        Non Visceral
    		 60 61 121
        Visceral
    		 247 253 500
    Hormone Receptor Status
    Units: Subjects
        Negative
    		 126 128 254
        Positive
    		 181 186 367
    Geographic Region
    Units: Subjects
        Europe
    		 121 123 244
        North America
    		 59 65 124
        Rest of World
    		 127 126 253
    Subject analysis sets

    Subject analysis set title
    Intent to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent to treat population is defined as all patients who are randomized into the study. Patients will be analyzed in the treatment arm to which they were randomly assigned regardless of which treatment they received.

    Subject analysis sets values
    		 Intent to treat population
    Number of subjects
    621
    Age categorical
    Units: Subjects
        <65 years
    492
        >=65 years
    129
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    54.67 ± 11.36
    Gender categorical
    Units: Subjects
        Female
    618
        Male
    3
    Previous HER2 Regimens
    Units: Subjects
        3 or more lines
    191
        2 lines
    430
    Disease Location
    Units: Subjects
        Non Visceral
    121
        Visceral
    500
    Hormone Receptor Status
    Units: Subjects
        Negative
    254
        Positive
    367
    Geographic Region
    Units: Subjects
        Europe
    244
        North America
    124
        Rest of World
    253

    End points

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    End points reporting groups
    Reporting group title
    Neratinib Plus Capecitabine
    Reporting group description
    		 Neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Reporting group title
    Lapatinib Plus Capecitabine
    Reporting group description
    		 Lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Subject analysis set title
    Intent to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent to treat population is defined as all patients who are randomized into the study. Patients will be analyzed in the treatment arm to which they were randomly assigned regardless of which treatment they received.

    Primary: Centrally Assessed Progression Free Survival

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    End point title
    		 Centrally Assessed Progression Free Survival
    End point description
    Progression Free Survival (PFS), Measured in Months, for Randomized Subjects of the Central Assessment. The time interval from the date of randomization until the first date on which recurrence, progression (per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) v1.1), or death due to any cause, is documented. For subjects without recurrence, progression or death, it is censored at the last valid tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 24 months.
    End point type
    Primary
    End point timeframe
    From randomization date to recurrence, progression or death, assessed up to 38 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    307
    314
    Units: months
        number (confidence interval 95%)
    8.8 (7.8 to 9.8)
    6.6 (5.9 to 7.4)
    Statistical analysis title
    		 PFS (LogRank Pvalue and Hazard Ratio)
    Statistical analysis description
    Lapatinib Plus Capecitabine is the reference. LogRank P-value and Hazard Ratio are stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
    Comparison groups
    Neratinib Plus Capecitabine v Lapatinib Plus Capecitabine
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0059
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.762
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.626
         upper limit
    		 0.926

    Primary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival (OS) is defined as the time from randomization to death due to any cause, censored at the last date known alive on or prior to the data cutoff employed for the analysis, whichever was earlier. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 48 months.
    End point type
    Primary
    End point timeframe
    From randomization date to death, assessed up to 59 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    307
    314
    Units: months
        number (confidence interval 95%)
    24.0 (22.1 to 25.9)
    22.2 (20.4 to 24.0)
    Statistical analysis title
    		 Overall Survival (LogRank Pvalue and Hazard Ratio)
    Statistical analysis description
    Lapatinib Plus Capecitabine is the reference. LogRank P-value and Hazard Ratio are stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
    Comparison groups
    Neratinib Plus Capecitabine v Lapatinib Plus Capecitabine
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2086
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.881
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.723
         upper limit
    		 1.073

    Secondary: Intervention for Symptomatic Metastatic Central Nervous System Disease

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    End point title
    		 Intervention for Symptomatic Metastatic Central Nervous System Disease
    End point description
    Intervention for symptomatic metastatic central nervous system disease is defined as the time from randomization to the first start date of an intervention for symptomatic metastatic CNS disease. Subjects that do not have an intervention for symptomatic metastatic CNS and do not die will be censored at the last date known alive on or prior to the data cutoff. Deaths are treated as competing events. Percentage of participants with intervention for CNS, estimated by cumulative incidence methods. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring.
    End point type
    Secondary
    End point timeframe
    From randomization date to first intervention for symptomatic metastatic CNS disease, assessed up to 59 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    307
    314
    Units: percentage of participants
        number (confidence interval 95%)
    22.76 (15.48 to 30.91)
    29.19 (22.54 to 36.14)
    Statistical analysis title
    		 Gray's Test: Intervention for Symptomatic CNS
    Statistical analysis description
    Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral disease.
    Comparison groups
    Neratinib Plus Capecitabine v Lapatinib Plus Capecitabine
    Number of subjects included in analysis
    621
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 Gray's Test
    Confidence interval

    Secondary: Objective Response Rate (ORR) - Central Assessment (ITT Population With Measurable Disease at Screening)

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    End point title
    		 Objective Response Rate (ORR) - Central Assessment (ITT Population With Measurable Disease at Screening)
    End point description
    Objective response rate is defined as the percentage of participants demonstrating an objective response during the study. Objective response includes confirmed complete responses (CR) and partial responses (PR) as defined in the RECIST criteria included in the study protocol. The ORR is for Central Assessment for subjects that had measurable disease at screening. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    End point type
    Secondary
    End point timeframe
    From randomization date to first confirmed Complete or Partial Response, whichever came earlier, up to 42 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    256
    270
    Units: percentage of participants
        number (confidence interval 95%)
    32.8 (27.1 to 38.9)
    26.7 (21.5 to 32.4)
    Statistical analysis title
    		 Objective Response Rate: CMH and Rate Difference
    Statistical analysis description
    Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral.
    Comparison groups
    Neratinib Plus Capecitabine v Lapatinib Plus Capecitabine
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1201
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 difference in rate (or proportions)
    Point estimate
    6.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 14.64

    Secondary: Clinical Benefit Rate (CBR) - Central Assessment (ITT Population With Measurable Disease at Screening)

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    End point title
    		 Clinical Benefit Rate (CBR) - Central Assessment (ITT Population With Measurable Disease at Screening)
    End point description
    Clinical benefit rate is the percentage of participants who achieve overall tumor response (confirmed CR or PR) or stable disease (SD) lasting for at least 24 weeks from randomization. The CBR was for Central Assessment for subjects who had Measurable Disease at Screening.
    End point type
    Secondary
    End point timeframe
    From randomization date to either first confirmed CR or PR or Stable Disease, whichever came earlier, up to 42 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    256
    270
    Units: percentage of participants
        number (confidence interval 95%)
    44.5 (38.3 to 50.8)
    35.6 (29.8 to 41.6)
    Statistical analysis title
    		 Clinical Benefit Rate: CMH and Rate Difference
    Statistical analysis description
    Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral.
    Comparison groups
    Lapatinib Plus Capecitabine v Neratinib Plus Capecitabine
    Number of subjects included in analysis
    526
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0328
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 difference in rate (or proportions)
    Point estimate
    8.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 17.43

    Secondary: Duration of Response (DOR) - Central Assessment (Population that Had a Response With Measurable Disease at Screening)

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    End point title
    		 Duration of Response (DOR) - Central Assessment (Population that Had a Response With Measurable Disease at Screening)
    End point description
    The Duration of Response (DOR) is for Central Assessment for the Population that Had a Response with Measurable Disease at Screening. Duration of response is measured from the time at which measurement criteria are first met for CR or PR (whichever status is recorded first) until the first date of recurrence or progressive disease (PD) or death is objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST v1.1. This value is censored at the last valid tumor assessment if PD or death has not been documented
    End point type
    Secondary
    End point timeframe
    From start date of response after randomization to first PD, up to 33 months. The result is based on primary analysis data cut on 28Sep2018.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    84
    72
    Units: months
        median (confidence interval 95%)
    8.54 (5.62 to 11.17)
    5.55 (4.21 to 6.41)
    Statistical analysis title
    		 Duration of Response: LogRank Pvalue and HR
    Statistical analysis description
    Lapatanib Plus Capecitabine is the reference.
    Comparison groups
    Neratinib Plus Capecitabine v Lapatinib Plus Capecitabine
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.495
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.332
         upper limit
    		 0.736

    Secondary: Percentage of Participants With Any Treatment-Emergent Adverse Events (Safety Population)

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    End point title
    		 Percentage of Participants With Any Treatment-Emergent Adverse Events (Safety Population)
    End point description
    Adverse Events to be measured are Any Treatment-Emergent Adverse Events that occurred on or after first dose of investigational product and up to 28 days after the last dose. Safety population: Participants receiving at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From time of first dose, through 28 days after last dose, assessed up to 41 months. The result is based on the final data cut of 18Dec2019. Last patient last visit (LPLV) is 9Dec2019.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    303
    311
    Units: percentage of participants
        number (not applicable)
    99.7
    99.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serious Treatment-Emergent Adverse Events (Safety Population)

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    End point title
    		 Percentage of Participants With Serious Treatment-Emergent Adverse Events (Safety Population)
    End point description
    Adverse Events to be measured are Serious Treatment-Emergent AEs that occurred on or after first dose of investigational product and up to 28 days after the last dose. Safety population: Participants receiving at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    From first dose through last dose + 28 days, up to 41 months. The result is based on final data cut on 18Dec2019. Last patient last visit (LPLV) is 9Dec2019.
    End point values
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Number of subjects analysed
    303
    311
    Units: percentage of participants
        number (not applicable)
    34.0
    29.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose through last dose + 28 days, up to 41 months. The result is based on final data cut.
    Adverse event reporting additional description
    Safety population: Participants receiving at least 1 dose of investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Neratinib Plus Capecitabine
    Reporting group description
    		 Neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Reporting group title
    Lapatinib Plus Capecitabine
    Reporting group description
    		 Lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.

    Serious adverse events
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 303 (33.99%)
    93 / 311 (29.90%)
         number of deaths (all causes)
    216
    240
         number of deaths resulting from adverse events
    8
    10
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    6 / 303 (1.98%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis malignant
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Abasia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Malaise
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suprapubic pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 303 (0.66%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    10 / 303 (3.30%)
    11 / 311 (3.54%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 303 (0.66%)
    7 / 311 (2.25%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood potassium increased
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 303 (0.66%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar syndrome
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 303 (0.33%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological decompensation
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nerve root compression
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 303 (1.32%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord oedema
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Syncope
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonic convulsion
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         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
    Anaemia
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 311 (0.96%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         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
    1 / 303 (0.33%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    22 / 303 (7.26%)
    13 / 311 (4.18%)
         occurrences causally related to treatment / all
    31 / 32
    15 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 303 (2.31%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    11 / 11
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    9 / 303 (2.97%)
    6 / 311 (1.93%)
         occurrences causally related to treatment / all
    7 / 9
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Bile duct obstruction
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis fulminant
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Jaundice
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin necrosis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    7 / 303 (2.31%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    4 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 303 (0.33%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 303 (0.33%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cellulitis
         subjects affected / exposed
    4 / 303 (1.32%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 303 (1.98%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 303 (0.33%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 311 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 303 (1.32%)
    5 / 311 (1.61%)
         occurrences causally related to treatment / all
    3 / 4
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 303 (0.66%)
    4 / 311 (1.29%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 311 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 311 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    301 / 303 (99.34%)
    309 / 311 (99.36%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 303 (8.91%)
    22 / 311 (7.07%)
         occurrences all number
    39
    35
    Aspartate aminotransferase increased
         subjects affected / exposed
    29 / 303 (9.57%)
    28 / 311 (9.00%)
         occurrences all number
    42
    42
    Blood bilirubin increased
         subjects affected / exposed
    18 / 303 (5.94%)
    34 / 311 (10.93%)
         occurrences all number
    36
    97
    Weight decreased
         subjects affected / exposed
    60 / 303 (19.80%)
    41 / 311 (13.18%)
         occurrences all number
    101
    60
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    43 / 303 (14.19%)
    30 / 311 (9.65%)
         occurrences all number
    52
    34
    Dysgeusia
         subjects affected / exposed
    17 / 303 (5.61%)
    13 / 311 (4.18%)
         occurrences all number
    18
    16
    Headache
         subjects affected / exposed
    32 / 303 (10.56%)
    50 / 311 (16.08%)
         occurrences all number
    34
    62
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    23 / 303 (7.59%)
    16 / 311 (5.14%)
         occurrences all number
    55
    43
    Anaemia
         subjects affected / exposed
    45 / 303 (14.85%)
    50 / 311 (16.08%)
         occurrences all number
    76
    105
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    36 / 303 (11.88%)
    34 / 311 (10.93%)
         occurrences all number
    86
    56
    Fatigue
         subjects affected / exposed
    102 / 303 (33.66%)
    97 / 311 (31.19%)
         occurrences all number
    149
    140
    Oedema peripheral
         subjects affected / exposed
    16 / 303 (5.28%)
    21 / 311 (6.75%)
         occurrences all number
    22
    23
    Pyrexia
         subjects affected / exposed
    32 / 303 (10.56%)
    32 / 311 (10.29%)
         occurrences all number
    37
    40
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    37 / 303 (12.21%)
    42 / 311 (13.50%)
         occurrences all number
    60
    53
    Abdominal distension
         subjects affected / exposed
    25 / 303 (8.25%)
    9 / 311 (2.89%)
         occurrences all number
    31
    11
    Abdominal pain upper
         subjects affected / exposed
    18 / 303 (5.94%)
    28 / 311 (9.00%)
         occurrences all number
    23
    36
    Constipation
         subjects affected / exposed
    95 / 303 (31.35%)
    40 / 311 (12.86%)
         occurrences all number
    142
    45
    Diarrhoea
         subjects affected / exposed
    248 / 303 (81.85%)
    205 / 311 (65.92%)
         occurrences all number
    1260
    629
    Dry mouth
         subjects affected / exposed
    15 / 303 (4.95%)
    18 / 311 (5.79%)
         occurrences all number
    15
    18
    Dyspepsia
         subjects affected / exposed
    20 / 303 (6.60%)
    29 / 311 (9.32%)
         occurrences all number
    23
    30
    Nausea
         subjects affected / exposed
    161 / 303 (53.14%)
    130 / 311 (41.80%)
         occurrences all number
    280
    206
    Stomatitis
         subjects affected / exposed
    63 / 303 (20.79%)
    83 / 311 (26.69%)
         occurrences all number
    104
    127
    Vomiting
         subjects affected / exposed
    138 / 303 (45.54%)
    95 / 311 (30.55%)
         occurrences all number
    256
    163
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    13 / 303 (4.29%)
    20 / 311 (6.43%)
         occurrences all number
    14
    21
    Dyspnoea
         subjects affected / exposed
    19 / 303 (6.27%)
    26 / 311 (8.36%)
         occurrences all number
    27
    34
    Cough
         subjects affected / exposed
    41 / 303 (13.53%)
    34 / 311 (10.93%)
         occurrences all number
    47
    36
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    13 / 303 (4.29%)
    23 / 311 (7.40%)
         occurrences all number
    14
    26
    Dry skin
         subjects affected / exposed
    20 / 303 (6.60%)
    15 / 311 (4.82%)
         occurrences all number
    25
    15
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    139 / 303 (45.87%)
    175 / 311 (56.27%)
         occurrences all number
    397
    468
    Rash
         subjects affected / exposed
    31 / 303 (10.23%)
    69 / 311 (22.19%)
         occurrences all number
    37
    95
    Skin fissures
         subjects affected / exposed
    9 / 303 (2.97%)
    19 / 311 (6.11%)
         occurrences all number
    13
    33
    Pruritus
         subjects affected / exposed
    26 / 303 (8.58%)
    25 / 311 (8.04%)
         occurrences all number
    31
    26
    Skin hyperpigmentation
         subjects affected / exposed
    7 / 303 (2.31%)
    17 / 311 (5.47%)
         occurrences all number
    7
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    20 / 303 (6.60%)
    23 / 311 (7.40%)
         occurrences all number
    22
    25
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    29 / 303 (9.57%)
    20 / 311 (6.43%)
         occurrences all number
    36
    29
    Back pain
         subjects affected / exposed
    30 / 303 (9.90%)
    22 / 311 (7.07%)
         occurrences all number
    38
    32
    Musculoskeletal pain
         subjects affected / exposed
    19 / 303 (6.27%)
    14 / 311 (4.50%)
         occurrences all number
    24
    14
    Pain in extremity
         subjects affected / exposed
    25 / 303 (8.25%)
    21 / 311 (6.75%)
         occurrences all number
    28
    29
    Infections and infestations
    Paronychia
         subjects affected / exposed
    35 / 303 (11.55%)
    49 / 311 (15.76%)
         occurrences all number
    71
    95
    Urinary tract infection
         subjects affected / exposed
    27 / 303 (8.91%)
    12 / 311 (3.86%)
         occurrences all number
    36
    12
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 303 (8.58%)
    14 / 311 (4.50%)
         occurrences all number
    33
    21
    Viral upper respiratory tract infection
         subjects affected / exposed
    20 / 303 (6.60%)
    23 / 311 (7.40%)
         occurrences all number
    23
    26
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    107 / 303 (35.31%)
    67 / 311 (21.54%)
         occurrences all number
    153
    88
    Dehydration
         subjects affected / exposed
    14 / 303 (4.62%)
    16 / 311 (5.14%)
         occurrences all number
    31
    18
    Hypokalaemia
         subjects affected / exposed
    35 / 303 (11.55%)
    41 / 311 (13.18%)
         occurrences all number
    51
    71

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2013
    The purpose of this amendment is to address the comments resulting from the SPA review by FDA of Amendment 2 dated 8 July, 2013, regarding the timing of start of first dose of study drug after randomization; Correct the trade name of the fluorescence in situ hybridization kit used for identifying HER2 mutations; Revise/correct dose adjustment Tables A2.7, A2.8, and A2.9 in Appendix 2; Perform an administrative text change in footnote “a” of Table A1.1 and in Appendix 7 regarding the timing of the baseline tumor assessments relative to randomization and treatment to be aligned with the previously agreed changes in Section 8.1.2.1.; Make other minor administrative/typographic changes where applicable.
    13 Feb 2014
    The purpose of this amendment is to increase the number of study sites; Adjust the prior cumulative anthracycline dose that a patient could have received; Reduce the time interval between the end of a prior therapy and initiation of study therapy from ≥28 days to ≥21 days; Change the time between completion of baseline assessments and randomization; Change the acceptable type of tumor tissue specimen that can be submitted for HER2 and ER/PR testing and the stage of disease at which it was obtained during a patient’s cancer history; Clarify that patients who discontinue study therapy and have not progressed will continue tumor assessments per protocol until disease progression and are followed up for survival; Clarify the frequency of tumor scans after a patient has a confirmed complete response; Make other minor typographic, grammatical, and administrative changes as necessary.

    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.
    The reported efficacy results include data collected up to the clinical data cut-off date of 28 Sep 2018. The safety results include all data up to study close on 9 Dec 2019.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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