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    Clinical Trial Results:
    LUX-Breast 2: An open-label, multinational, phase-II trial of Afatinib (BIBW 2992) in patients with metastatic human epidermal growth factor receptor (HER2) - overexpressing breast cancer failing HER2 - targeted treatment in the neoadjuvant and/or adjuvant treatment setting

    Summary
    EudraCT number
    		 2010-021945-29
    Trial protocol
    		 GB  
    Global end of trial date
    13 Mar 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Jun 2022
    First version publication date
    24 Mar 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Correction to previously submitted information.

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.98
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01271725
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.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
    10 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of afatinib alone, and of afatinib in combination with weekly paclitaxel or vinorelbine upon progression on afatinib monotherapy, in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted treatment in the adjuvant and/or neoadjuvant setting.
    Protection of trial subjects
    All patients were informed that they were free to withdraw their consent at any time during the study without penalty or prejudice. The patients were informed that their personal trial related data would be considered confidential and used by BI in accordance with the local data protection laws. The level of disclosure was explained to the patients. The patients were also informed that their medical records could be examined by Clinical Quality Assurance auditors appointed by BI, by members of the appropriate IEC/IRB, and by inspectors from regulatory authorities. Confidentiality of patient data was ensured by the use of depersonalised patient identification codes (patient numbers). The terms and conditions of the insurance cover were available to the investigator and the patients in the Investigator Site File.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    India: 19
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Taiwan: 32
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    87
    EEA total number of subjects
    9
    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)
    77
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 An open-label, multinational, phase-II trial of Afatinib (BIBW 2992) in patients with metastatic human epidermal growth factor receptor (HER2) - overexpressing breast cancer failing HER2 - targeted treatment in the neoadjuvant and/or adjuvant treatment setting

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist sites which ensured that they met all strictly implemented inclusion/exclusion criteria. Subjects were not to be entered to trial treatment if any one of the specific entry criteria was violated.

    Period 1
    Period 1 title
    Part A
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    An open-label trial

    Arms
    Arm title
    		 Afatinib monotherapy
    Arm description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) filmcoated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal

    Number of subjects in period 1 [1]
    		Afatinib monotherapy
    Started
    74
    Completed
    39
    Not completed
    35
         Adverse event, serious fatal
    3
         Consent withdrawn by subject
    12
         Adverse event, non-fatal
    5
         Other than specified
    3
         Clinical signs/symptoms of progression
    2
         Lost to follow-up
    1
         Progressive disease according to RECIST
    8
         Protocol deviation
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 87 enrolled subjects only 74 were randomized.
    Period 2
    Period 2 title
    Part B
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    An open-label trial

    Arms
    Arm title
    		 Afatinib and Paclitaxel or Vinorelbine combination therapy
    Arm description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient received 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly.

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient received 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly.

    Number of subjects in period 2
    		Afatinib and Paclitaxel or Vinorelbine combination therapy
    Started
    39
    Completed
    27
    Not completed
    12
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    1
         Other than specified
    2
         Clinical signs/symptoms of progression
    2
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Afatinib monotherapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) filmcoated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated.

    Reporting group values
    		 Afatinib monotherapy Total
    Number of subjects
    		 74 74
    Age categorical
    The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.
    Units: Subjects
    Age Continuous
    Age at the time of signing informed consent form is presented. The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine. The baseline population analysis set was Treated set.
    Units: years
        arithmetic mean (standard deviation)
    		 51.3 ± 10.6 -
    Sex: Female, Male
    Number of subjects is categorized as Male or Female. The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.
    Units: Subjects
        Female
    		 74 74
        Male
    		 0 0
    Race (NIH/OMB)
    Ethnicity was not captured in this trial. The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 47 47
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 27 27
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0

    End points

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    End points reporting groups
    Reporting group title
    Afatinib monotherapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) filmcoated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated.
    Reporting group title
    Afatinib and Paclitaxel or Vinorelbine combination therapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy

    Subject analysis set title
    Afatinib and Vinorelbine combination therapy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy

    Subject analysis set title
    Afatinib and Paclitaxel combination therapy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy

    Primary: Objective Response (OR) assessed by Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1

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    End point title
    		 Objective Response (OR) assessed by Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1 [1]
    End point description
    Objective response according to RECIST v1.1. Best overall response of confirmed complete response (CR) or confirmed partial response (PR) recorded since first administration of trial medication and until the earliest of disease progression, death or start of next treatment in each part separately. Percentage of participants with OR along with exact 95% Confidence Interval by Clopper and Pearson is presented. The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.
    End point type
    Primary
    End point timeframe
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    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: Endpoint was analyzed only descriptively.
    End point values
    		 Afatinib monotherapy Afatinib and Paclitaxel or Vinorelbine combination therapy
    Number of subjects analysed
    74 [2]
    39 [3]
    Units: Percentage
        number (confidence interval 95%)
    18 (10 to 28)
    31 (17 to 48)
    Notes
    [2] - Treated Set
    [3] - Treated Set
    No statistical analyses for this end point

    Secondary: Best Overall Response According to RECIST v1.1 (With confirmation)

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    End point title
    		 Best Overall Response According to RECIST v1.1 (With confirmation)
    End point description
    Best overall response is the best overall response to trial medication according to RECIST version 1.1 and was calculated relative to the baseline of each respective part. Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR) & gt;=30% decrease in the sum of the longest diameter of target lesions; progression, 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
    End point type
    Secondary
    End point timeframe
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    End point values
    		 Afatinib monotherapy Afatinib and Paclitaxel or Vinorelbine combination therapy
    Number of subjects analysed
    74 [4]
    39 [5]
    Units: Percentage
    number (confidence interval 95%)
        Complete response (CR)|
    1 (0 to 7)
    0 (0 to 9)
        Partial response (PR)|
    16 (9 to 27)
    31 (17 to 48)
        Stable disease (SD)|
    45 (33 to 57)
    46 (30 to 63)
        Progressive disease|
    28 (19 to 40)
    10 (3 to 24)
        Not evaluable|
    9 (4 to 19)
    13 (4 to 27)
    Notes
    [4] - Treated set
    [5] - Treated set
    No statistical analyses for this end point

    Secondary: Best Overall Response According to RECIST v1.1 (Regardless of confirmation)

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    End point title
    		 Best Overall Response According to RECIST v1.1 (Regardless of confirmation)
    End point description
    Best overall response is the best overall response to trial medication (without clinical disease assessment) according to RECIST version 1.1 and was calculated relative to the baseline of each respective part. Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR) & gt;=30% decrease in the sum of the longest diameter of target lesions; progression, 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
    End point type
    Secondary
    End point timeframe
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    End point values
    		 Afatinib monotherapy Afatinib and Paclitaxel or Vinorelbine combination therapy
    Number of subjects analysed
    74 [6]
    39 [7]
    Units: Percentage
    number (confidence interval 95%)
        Complete response (CR)|
    1 (0 to 7)
    0 (0 to 9)
        Partial response (PR)|
    19 (11 to 30)
    44 (28 to 60)
        Stable disease (SD)|
    42 (31 to 54)
    33 (19 to 50)
        Progressive disease|
    28 (19 to 40)
    10 (3 to 24)
        Not evaluable|
    9 (4 to 19)
    13 (4 to 27)
    Notes
    [6] - Treated Set
    [7] - Treated Set
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    Progression Free Survival is defined as the time from the drug start date to the date of 1st disease progression or death for monotherapy and 2nd disease progression or death from the drug start date of the combination therapy for combination therapy'. Median is calculated from the Kaplan−Meier curve.
    End point type
    Secondary
    End point timeframe
    From drug start date in monotherapy to 1st disease progression and drug start date in combination therapy to 2nd disease progression
    End point values
    		 Afatinib monotherapy Afatinib and Paclitaxel or Vinorelbine combination therapy
    Number of subjects analysed
    74 [8]
    39 [9]
    Units: Days
        median (confidence interval 95%)
    86.0 (72.0 to 127.0)
    135.0 (95.0 to 224.0)
    Notes
    [8] - Treated Set
    [9] - Treated Set
    No statistical analyses for this end point

    Secondary: Duration of Objective Response according to RECIST v1.1

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    End point title
    		 Duration of Objective Response according to RECIST v1.1
    End point description
    Duration of objective response, defined as the time from first objective response to the time of progression or death. (regardless of confirmation)
    End point type
    Secondary
    End point timeframe
    From the first objective response to the time of progression or death
    End point values
    		 Afatinib monotherapy Afatinib and Paclitaxel or Vinorelbine combination therapy
    Number of subjects analysed
    74 [10]
    39 [11]
    Units: Days
        median (confidence interval 95%)
    168.5 (85.0 to 253.0)
    125.0 (73.0 to 505.0)
    Notes
    [10] - Treated Set
    [11] - Treated Set
    No statistical analyses for this end point

    Secondary: Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher

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    End point title
    		 Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher
    End point description
    Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher.
    End point type
    Secondary
    End point timeframe
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    End point values
    		 Afatinib monotherapy Afatinib and Vinorelbine combination therapy Afatinib and Paclitaxel combination therapy
    Number of subjects analysed
    74 [12]
    13 [13]
    26 [14]
    Units: Percentage
    43
    62
    65
    Notes
    [12] - Treated Set
    [13] - Treated Set
    [14] - Treated Set
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in systolic blood pressure (SBP)

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    End point title
    		 Change from baseline to end of treatment in systolic blood pressure (SBP)
    End point description
    Change from baseline to end of treatment in systolic blood pressure (SBP).
    End point type
    Secondary
    End point timeframe
    Baseline and End of treatment period
    End point values
    		 Afatinib monotherapy Afatinib and Vinorelbine combination therapy Afatinib and Paclitaxel combination therapy
    Number of subjects analysed
    74 [15]
    13 [16]
    26 [17]
    Units: Millimeter of mercury (mmHg)
        arithmetic mean (standard deviation)
    -1.2 ± 17.9
    -1.0 ± 15.1
    -3.7 ± 12.1
    Notes
    [15] - Treated Set
    [16] - Treated Set
    [17] - Treated Set
    No statistical analyses for this end point

    Secondary: Change from baseline to end of treatment in diastolic blood pressure (DBP)

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    End point title
    		 Change from baseline to end of treatment in diastolic blood pressure (DBP)
    End point description
    Change from baseline to end of treatment in diastolic blood pressure (DBP).
    End point type
    Secondary
    End point timeframe
    Baseline and End of treatment period
    End point values
    		 Afatinib monotherapy Afatinib and Vinorelbine combination therapy Afatinib and Paclitaxel combination therapy
    Number of subjects analysed
    74 [18]
    13 [19]
    26 [20]
    Units: Millimeter of mercury (mmHg)
        arithmetic mean (standard deviation)
    -1.8 ± 12.0
    1.9 ± 10.7
    -1.6 ± 10.0
    Notes
    [18] - Treated Set
    [19] - Treated Set
    [20] - Treated Set
    No statistical analyses for this end point

    Secondary: Number of patient with possibly clinically significant (PCS) laboratory values

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    End point title
    		 Number of patient with possibly clinically significant (PCS) laboratory values
    End point description
    Number of patient with possibly clinically significant (PCS) laboratory values by functional group (haematology, differentials, coagulation, electrolytes, enzymes, and substrates). These findings were reported as adverse events. 99999: Not Applicable
    End point type
    Secondary
    End point timeframe
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    End point values
    		 Afatinib monotherapy Afatinib and Vinorelbine combination therapy Afatinib and Paclitaxel combination therapy
    Number of subjects analysed
    74 [21]
    13 [22]
    26 [23]
    Units: Number of Participants
        Weight decreased|
    10
    1
    4
        Alanine aminotransferase increased|
    5
    0
    4
        Neutrophil count decreased|
    99999
    2
    1
        Aspartate aminotransferase increased|
    3
    1
    3
        Alanine aminotransferase|
    99999
    1
    0
        Aspartate aminotransferase|
    99999
    1
    0
        Blood creatinine increased|
    2
    0
    2
        Blood glucose decreased|
    99999
    1
    0
        Blood lactate dehydrogenase increased|
    2
    0
    2
        Blood uric acid increased|
    2
    0
    2
        Blood calcium decreased|
    99999
    0
    1
        Blood sodium decreased|
    1
    0
    1
        Haemoglobin decreased|
    3
    0
    1
        Urine output decreased|
    99999
    0
    1
        White blood cell count decreased|
    1
    0
    1
        Blood alkaline phosphatase increased|
    4
    99999
    99999
        Blood alkaline phosphatase|
    1
    99999
    99999
        Blood creatine phosphokinase increased|
    1
    99999
    99999
        Blood lactic acid increased|
    1
    99999
    99999
        Blood potassium decreased|
    1
    99999
    99999
        Glomerular filtration rate decreased|
    1
    99999
    99999
        Liver function test increased|
    1
    99999
    99999
        Lymphocyte count decreased|
    1
    99999
    99999
        Platelet count decreased|
    1
    99999
    99999
        Red blood cell sedimentation rate increased|
    1
    99999
    99999
    Notes
    [21] - Treated Set
    [22] - Treated Set
    [23] - Treated Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
    Adverse event reporting additional description
    Safety analyses were performed for monotherapy and combination therapy separately using the respective treated sets. Treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each afatinib/paclitaxel or afatinib/vinorelbine.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Afatinib monotherapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated.

    Reporting group title
    Afatinib and Paclitaxel combination therapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy

    Reporting group title
    Afatinib and Vinorelbine combination therapy
    Reporting group description
    		 Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (A dose reduction to 30mg and 20mg was possible if 40mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy

    Serious adverse events
    		 Afatinib monotherapy Afatinib and Paclitaxel combination therapy Afatinib and Vinorelbine combination therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 74 (24.32%)
    10 / 26 (38.46%)
    5 / 13 (38.46%)
         number of deaths (all causes)
    6
    5
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Dyspnoea
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 26 (0.00%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Pleural effusion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Respiratory arrest
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Respiratory failure
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Product issues
    Device leakage
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Device occlusion
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Dizziness
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Neuralgia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Seizure
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Anaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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 and urinary disorders
    Azotaemia
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 74 (1.35%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Diarrhoea infectious
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Herpes zoster
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Liver abscess
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    0 / 13 (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
    Urosepsis
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    0 / 13 (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
    Decreased appetite
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    		 Afatinib monotherapy Afatinib and Paclitaxel combination therapy Afatinib and Vinorelbine combination therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 74 (90.54%)
    23 / 26 (88.46%)
    13 / 13 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm progression
         subjects affected / exposed
    6 / 74 (8.11%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    6
    1
    0
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 74 (6.76%)
    7 / 26 (26.92%)
    2 / 13 (15.38%)
         occurrences all number
    5
    8
    8
    Fatigue
         subjects affected / exposed
    7 / 74 (9.46%)
    5 / 26 (19.23%)
    0 / 13 (0.00%)
         occurrences all number
    7
    5
    0
    Mucosal inflammation
         subjects affected / exposed
    15 / 74 (20.27%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    22
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    Oedema
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    4 / 74 (5.41%)
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    5
    2
    2
    Ulcer
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 74 (10.81%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    8
    4
    0
    Dyspnoea
         subjects affected / exposed
    8 / 74 (10.81%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    8
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    3
    2
    0
    Epistaxis
         subjects affected / exposed
    6 / 74 (8.11%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    6
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    Investigations
    Alanine aminotransferase
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    5
    6
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 26 (11.54%)
    1 / 13 (7.69%)
         occurrences all number
    3
    3
    1
    Aspartate aminotransferase
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    0
    Blood glucose decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    3
    Blood uric acid increased
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    3
    2
    0
    Weight decreased
         subjects affected / exposed
    10 / 74 (13.51%)
    4 / 26 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    11
    5
    1
    Injury, poisoning and procedural complications
    Wound
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Wound secretion
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 74 (9.46%)
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    8
    5
    1
    Dizziness
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 26 (11.54%)
    1 / 13 (7.69%)
         occurrences all number
    3
    3
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 74 (0.00%)
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 74 (9.46%)
    13 / 26 (50.00%)
    4 / 13 (30.77%)
         occurrences all number
    7
    17
    4
    Leukopenia
         subjects affected / exposed
    1 / 74 (1.35%)
    5 / 26 (19.23%)
    4 / 13 (30.77%)
         occurrences all number
    2
    7
    7
    Neutropenia
         subjects affected / exposed
    1 / 74 (1.35%)
    9 / 26 (34.62%)
    9 / 13 (69.23%)
         occurrences all number
    1
    36
    24
    Thrombocytopenia
         subjects affected / exposed
    2 / 74 (2.70%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 74 (4.05%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    5
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 74 (1.35%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    Anal inflammation
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 74 (0.00%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Diarrhoea
         subjects affected / exposed
    50 / 74 (67.57%)
    9 / 26 (34.62%)
    3 / 13 (23.08%)
         occurrences all number
    101
    18
    4
    Haemorrhoids
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    3
    2
    1
    Nausea
         subjects affected / exposed
    9 / 74 (12.16%)
    4 / 26 (15.38%)
    1 / 13 (7.69%)
         occurrences all number
    9
    13
    1
    Mouth ulceration
         subjects affected / exposed
    8 / 74 (10.81%)
    2 / 26 (7.69%)
    2 / 13 (15.38%)
         occurrences all number
    8
    2
    2
    Vomiting
         subjects affected / exposed
    6 / 74 (8.11%)
    4 / 26 (15.38%)
    2 / 13 (15.38%)
         occurrences all number
    6
    5
    2
    Stomatitis
         subjects affected / exposed
    3 / 74 (4.05%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    0
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 74 (6.76%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    6
    0
    0
    Alopecia
         subjects affected / exposed
    2 / 74 (2.70%)
    10 / 26 (38.46%)
    1 / 13 (7.69%)
         occurrences all number
    2
    10
    1
    Dermatitis
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences all number
    5
    1
    2
    Eczema
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    5
    1
    2
    Eczema asteatotic
         subjects affected / exposed
    1 / 74 (1.35%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Nail bed inflammation
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    13 / 74 (17.57%)
    3 / 26 (11.54%)
    1 / 13 (7.69%)
         occurrences all number
    15
    3
    1
    Pruritus
         subjects affected / exposed
    5 / 74 (6.76%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    6
    2
    0
    Rash
         subjects affected / exposed
    37 / 74 (50.00%)
    4 / 26 (15.38%)
    3 / 13 (23.08%)
         occurrences all number
    42
    8
    4
    Rash pruritic
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 26 (7.69%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    2
    Skin hyperpigmentation
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    3
    0
    Back pain
         subjects affected / exposed
    2 / 74 (2.70%)
    0 / 26 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    3
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 74 (0.00%)
    1 / 26 (3.85%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    5 / 74 (6.76%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    5
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    4 / 74 (5.41%)
    0 / 26 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    5
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 74 (1.35%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Paronychia
         subjects affected / exposed
    9 / 74 (12.16%)
    1 / 26 (3.85%)
    2 / 13 (15.38%)
         occurrences all number
    12
    6
    2
    Periodontitis
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 74 (0.00%)
    0 / 26 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 74 (5.41%)
    1 / 26 (3.85%)
    0 / 13 (0.00%)
         occurrences all number
    4
    3
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 74 (4.05%)
    3 / 26 (11.54%)
    0 / 13 (0.00%)
         occurrences all number
    3
    4
    0
    Viral infection
         subjects affected / exposed
    0 / 74 (0.00%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 74 (6.76%)
    4 / 26 (15.38%)
    0 / 13 (0.00%)
         occurrences all number
    5
    4
    0
    Hypocalcaemia
         subjects affected / exposed
    2 / 74 (2.70%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    2
    3
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 74 (4.05%)
    2 / 26 (7.69%)
    0 / 13 (0.00%)
         occurrences all number
    6
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2010
    The schedule for tumour assessments was clarified. Use of contraception post study for each of the trial medications was defined, at the request of the Competent Authorities and to align the text with the summaries of product characteristics (SmPCs) for paclitaxel and vinorelbine. Vinorelbine infusion time was clarified. An explanation was added regarding handling of hospitalisations for administrative reasons.
    27 Apr 2011
    It was clarified that haematology (complete blood count) results were required prior to chemotherapy. Guidance on the use of radiotherapy during the trial was added. Palliative radiotherapy became allowed. An exclusion criterion was amended to allow palliative radiotherapy. Guidance on the timing of study medication intake was corrected. The requirement for a platelet count value before treatment with paclitaxel was added. The adverse event reporting periods were corrected. It was clarified that the reference SmPC was not the local version.
    29 Jul 2011
    ‘LUX-Breast 2’ was added to the title to indicate that this trial is part of the LUX-breast program
    06 Dec 2011
    Text was added regarding drug-induced liver injury (DILI) in line with new corporate standards. An exclusion criterion was added to clarify that the intention was to include patients who required first-line treatment for metastatic breast cancer. Guidance on missed doses was added. Text was added regarding AE that are considered ‘always serious’ in line with new corporate standards.
    06 Nov 2012
    Timing of ECHO and MUGA scans during combination therapy was added and clarified. Guidance on the concomitant use of P-gp inhibitors and inducers- was updated, and a list medications in this class was added. Information about the incidence of keratitis in licensed epidermal growth factor receptor (EGFR) inhibitors was added. The requirement for a platelet count to be available prior to the start of each vinorelbine infusion was added, a statement on vinorelbine dose adjustment for severe hepatic impairment was added, and instructions for diluting vinorelbine were amended following the release of an updated SmPC for vinorelbine. The name of the manufacturer of paclitaxel was removed following a shortage of paclitaxel from Hospira United Kingdom. Reporting of worsening of underlying disease or other pre-existing conditions, change in vital signs, Electrocardiogram, physical examination and laboratory test results were modified for alignment with project standard definitions.
    27 Jun 2013
    The inclusion of patients after progression on Afatinib monotherapy (part A) into the afatinib + vinorelbine combination in Part B was stopped. Patients in part A could only go into the Afatinib + Paclitaxel arm. Enrolment of new patients into the trial was also stopped. The description of bottles of afatinib was removed in case future supplies were switched to the marketed product

    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.
    Enrollment of patients into the afatinib and vinorelbine combination option was stopped prematurely following a benefit-risk analysis in other trial. Any patients who were already benefiting from this combination were allowed to continue.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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