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    Clinical Trial Results:
    LUX-Lung 7: A randomised, open-label Phase IIb trial of afatinib versus gefitinib as first-line treatment of patients with EGFR mutation positive advanced adenocarcinoma of the lung

    Summary
    EudraCT number
    		 2011-001814-33
    Trial protocol
    		 SE   ES   DE   NO   GB   IE  
    Global end of trial date
    12 Apr 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Nov 2021
    First version publication date
    11 Apr 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01466660
    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 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 18002430127, 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
    08 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Dec 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
    United Kingdom: 12
    Country: Number of subjects enrolled
    Australia: 33
    Country: Number of subjects enrolled
    Canada: 92
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Spain: 93
    Country: Number of subjects enrolled
    France: 56
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    China: 63
    Country: Number of subjects enrolled
    Taiwan: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 89
    Country: Number of subjects enrolled
    Sweden: 40
    Country: Number of subjects enrolled
    Singapore: 31
    Worldwide total number of subjects
    571
    EEA total number of subjects
    219
    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)
    314
    From 65 to 84 years
    251
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Two-arm, randomised (1:1 ratio), open-label, parallel group trial. In the study disease response was assessed by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This open-label trial was treated as blinded by the trial team until database lock. Blinding of trial medication was not feasible because of differences in dose adjustments (dose adjustment scheme for afatinib, gefitinib was only available in one dose strength) and limitations in gefitinib packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Afatinib
    Arm description
    		 Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
    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
    Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Arm title
    		 Gefitinib
    Arm description
    		 Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gefitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Number of subjects in period 1 [1]
    		Afatinib Gefitinib
    Started
    160
    159
    Completed
    0
    0
    Not completed
    160
    159
         Other reason not defined above
    10
    8
         Refused continuation of trial medication
    4
    3
         Progressive Disease (RECIST 1.1)
    120
    127
         Other adverse event
    19
    18
         Worsening of underlying cancer disease
    5
    2
         Protocol deviation
    2
    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: 571 subjects were enrolled worldwide and thereof 252 not randomised. The remaining 319 subjects were randomised and treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 Randomised subjects.

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 319 319
    Age categorical
    Analysis set: All randomised subjects.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 177 177
        From 65-84 years
    		 138 138
        85 years and over
    		 4 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 62.4 ( 11.0 ) -
    Sex: Female, Male
    Units:
        Female
    		 197 197
        Male
    		 122 122
    Race (NIH/OMB)
    Analysis set: All randomised subjects. "Unknown or Not Reported" reflects the subjects in France where race was not recorded.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 182 182
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 1 1
        White
    		 102 102
        More than one race
    		 0 0
        Unknown or Not Reported
    		 34 34

    End points

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    End points reporting groups
    Reporting group title
    Afatinib
    Reporting group description
    		 Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Reporting group title
    Gefitinib
    Reporting group description
    		 Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.
    End point type
    Primary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [1]
    159 [2]
    Units: Months
        median (confidence interval 95%)
    12.78 (10.91 to 14.72)
    11.17 (9.49 to 12.81)
    Notes
    [1] - Randomised set included all subjects randomised to receive treatment.
    [2] - Randomised set included all subjects randomised to receive treatment.
    Statistical analysis title
    		 Time-to-event analysis
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.0891 [3]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.822
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.655
         upper limit
    		 1.032
    Notes
    [3] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Primary: Time to Treatment Failure (TTF) (main overall survival analysis cut-off date, 08 April 2016)

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    End point title
    		 Time to Treatment Failure (TTF) (main overall survival analysis cut-off date, 08 April 2016)
    End point description
    Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.
    End point type
    Primary
    End point timeframe
    From first drug administration until last drug administration, up to 1482 days
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [4]
    159 [5]
    Units: Months
        median (confidence interval 95%)
    13.67 (11.89 to 14.95)
    11.53 (10.09 to 13.11)
    Notes
    [4] - Randomised set included all subjects randomised to receive treatment.
    [5] - Randomised set included all subjects randomised to receive treatment.
    Statistical analysis title
    		 Time-to-event analysis
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.0136 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.595
         upper limit
    		 0.944
    Notes
    [6] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.
    End point type
    Primary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [7]
    159 [8]
    Units: Months
        median (confidence interval 95%)
    27.86 (25.13 to 32.85)
    24.54 (20.57 to 28.88)
    Notes
    [7] - Randomised set included all subjects randomised to receive treatment.
    [8] - Randomised set included all subjects randomised to receive treatment.
    Statistical analysis title
    		 Time-to-event analysis
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.2343 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.862
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.674
         upper limit
    		 1.101
    Notes
    [9] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Secondary: Objective response rate

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    End point title
    		 Objective response rate
    End point description
    Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [10]
    159 [11]
    Units: Percentage of participants
        number (confidence interval 95%)
    79.4 (72.3 to 85.4)
    74.8 (67.4 to 81.4)
    Notes
    [10] - Randomised set included all subjects randomised to receive treatment.
    [11] - Randomised set included all subjects randomised to receive treatment.
    Statistical analysis title
    		 Logistic regression analysis
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.3235 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.307
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.768
         upper limit
    		 2.223
    Notes
    [12] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Secondary: Time to objective response

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    End point title
    		 Time to objective response
    End point description
    Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    127 [13]
    119 [14]
    Units: Participants
        Week 4
    81
    74
        Week 8
    112
    107
        Week 16
    119
    117
        Week 24
    122
    118
        Week 32
    125
    118
        Week 40
    126
    118
        Week 48
    127
    119
    Notes
    [13] - All randomised subjects with objective response.
    [14] - All randomised subjects with objective response.
    No statistical analyses for this end point

    Secondary: Duration of objective response

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    End point title
    		 Duration of objective response
    End point description
    Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    127 [15]
    119 [16]
    Units: Months
        median (confidence interval 95%)
    11.86 (10.12 to 15.54)
    11.07 (9.69 to 12.91)
    Notes
    [15] - All randomised subjects with objective response.
    [16] - All randomised subjects with objective response.
    No statistical analyses for this end point

    Secondary: Disease control

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    End point title
    		 Disease control
    End point description
    Percentage of participants with disease control defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [17]
    159 [18]
    Units: Percentage of participants
        number (confidence interval 95%)
    94.4 (89.6 to 97.4)
    93.7 (88.7 to 96.9)
    Notes
    [17] - Randomised set included all subjects randomised to receive treatment.
    [18] - Randomised set included all subjects randomised to receive treatment.
    Statistical analysis title
    		 Logistic regression analysis
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    319
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.7856 [19]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.138
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.447
         upper limit
    		 2.896
    Notes
    [19] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Secondary: Duration of disease control

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    End point title
    		 Duration of disease control
    End point description
    Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment. All randomised subjects with disease control are all randomised subjects with best overall response of complete response or partial response or stable disease.
    End point type
    Secondary
    End point timeframe
    From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    151 [20]
    149 [21]
    Units: Months
        median (confidence interval 95%)
    12.88 (11.14 to 14.88)
    11.73 (10.58 to 14.55)
    Notes
    [20] - All randomised subjects with disease control.
    [21] - All randomised subjects with disease control.
    No statistical analyses for this end point

    Secondary: Tumour shrinkage (main overall survival analysis cut-off date, 08 April 2016)

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    End point title
    		 Tumour shrinkage (main overall survival analysis cut-off date, 08 April 2016)
    End point description
    Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.
    End point type
    Secondary
    End point timeframe
    From first drug administration until last drug administration, up to 1482 days
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    149 [22]
    151 [23]
    Units: millimetre (mm)
        least squares mean (confidence interval 95%)
    34.79 (32.18 to 37.40)
    38.25 (35.65 to 40.84)
    Notes
    [22] - All randomised subjects with tumour assessments.
    [23] - All randomised subjects with tumour assessments.
    Statistical analysis title
    		 Analysis of covariance
    Statistical analysis description
    Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.0657 [24]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.13
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.87
    Notes
    [24] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Secondary: Health-related quality of life (primary analysis cut-off date, 21 August 2015)

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    End point title
    		 Health-related quality of life (primary analysis cut-off date, 21 August 2015)
    End point description
    Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.
    End point type
    Secondary
    End point timeframe
    Every 8 weeks, up to 56 weeks
    End point values
    		 Afatinib Gefitinib
    Number of subjects analysed
    160 [25]
    158 [26]
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        EQ-5D UK utility score
    0.77 (0.75 to 0.80)
    0.80 (0.77 to 0.82)
        EQ-5D Belgium utility score
    0.74 (0.72 to 0.77)
    0.77 (0.75 to 0.80)
        EQ-VAS utility score
    74.5 (72.3 to 76.6)
    76.0 (73.9 to 78.1)
    Notes
    [25] - All randomised subjects with health-related quality of life data.
    [26] - All randomised subjects with health-related quality of life data.
    Statistical analysis title
    		 Mixed models analysis for EQ-5D UK
    Statistical analysis description
    EQ-5D UK utility score. Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.1422 [27]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.017
    Notes
    [27] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.
    Statistical analysis title
    		 Mixed models analysis for EQ-5D Belgium
    Statistical analysis description
    EQ-5D Belgium utility score. Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.054 [28]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016
    Notes
    [28] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.
    Statistical analysis title
    		 Mixed models analysis for EQ-VAS
    Statistical analysis description
    EQ-VAS utility score. Exploratory trial, no formal hypotheses were tested.
    Comparison groups
    Afatinib v Gefitinib
    Number of subjects included in analysis
    318
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 ≤ 0.2032 [29]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.21
    Notes
    [29] - p-value was not adjusted for multiple comparisons and was interpreted in an exploratory fashion.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 28 days after last drug administration, up to 2405 days. For All-Cause Mortality: From first drug administration until 28 days after last drug administration + Follow-Up period to collect death, up to 2465 days
    Adverse event reporting additional description
    Treated set included all subjects who were dispensed with and documented to have taken at least one dose of study medication. This set of subjects was used for the evaluation of safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Gefitinib
    Reporting group description
    		 Gefitinib film-coated tablets, administered orally, once daily. Starting dose was 250mg, the investigator was allowed to modify dosing in the presence of drug-related adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Reporting group title
    Afatinib
    Reporting group description
    		 Afatinib film-coated tablets administered orally, once daily. Starting dose was 40 milligram (mg), dose escalation to 50mg was allowed after completing one 28-day treatment course, dose reduction to 40mg, 30mg or 20mg was required in the presence of protocol-defined adverse events. Continuous daily dosing until disease progression, occurrence of unacceptable adverse events, or other reason necessitating withdrawal.

    Serious adverse events
    		 Gefitinib Afatinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    64 / 159 (40.25%)
    75 / 160 (46.88%)
         number of deaths (all causes)
    132
    126
         number of deaths resulting from adverse events
    10
    16
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 159 (0.63%)
    7 / 160 (4.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Metastases to central nervous system
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Renal cancer
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesteatoma
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Pneumonectomy
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 159 (1.26%)
    4 / 160 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (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
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 159 (3.14%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    4 / 159 (2.52%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    2 / 159 (1.26%)
    9 / 160 (5.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumothorax
         subjects affected / exposed
    3 / 159 (1.89%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 159 (3.14%)
    6 / 160 (3.75%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood sodium decreased
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         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 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foreign body aspiration
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (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 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin laceration
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         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 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 159 (3.14%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic cerebral infarction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorder
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraneoplastic encephalomyelitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    2 / 159 (1.26%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral disorder
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         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 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoid tissue hyperplasia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (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
    Sudden hearing loss
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (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 pain
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 159 (1.26%)
    11 / 160 (6.88%)
         occurrences causally related to treatment / all
    1 / 2
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 159 (0.00%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 159 (1.89%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatitis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intertrigo
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain of skin
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 159 (0.00%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Cushing's syndrome
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 159 (1.26%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         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
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         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 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 159 (0.63%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 159 (3.14%)
    7 / 160 (4.38%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    4 / 159 (2.52%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 159 (0.00%)
    2 / 160 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 159 (1.26%)
    0 / 160 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 159 (0.63%)
    0 / 160 (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
    1 / 159 (0.63%)
    3 / 160 (1.88%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 159 (0.63%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 159 (0.00%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Gefitinib Afatinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    159 / 159 (100.00%)
    157 / 160 (98.13%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    22 / 159 (13.84%)
    21 / 160 (13.13%)
         occurrences all number
    32
    35
    Chest pain
         subjects affected / exposed
    19 / 159 (11.95%)
    20 / 160 (12.50%)
         occurrences all number
    20
    26
    Fatigue
         subjects affected / exposed
    30 / 159 (18.87%)
    34 / 160 (21.25%)
         occurrences all number
    38
    37
    Influenza like illness
         subjects affected / exposed
    8 / 159 (5.03%)
    3 / 160 (1.88%)
         occurrences all number
    10
    3
    Mucosal inflammation
         subjects affected / exposed
    19 / 159 (11.95%)
    32 / 160 (20.00%)
         occurrences all number
    26
    54
    Oedema peripheral
         subjects affected / exposed
    10 / 159 (6.29%)
    11 / 160 (6.88%)
         occurrences all number
    11
    12
    Pyrexia
         subjects affected / exposed
    10 / 159 (6.29%)
    22 / 160 (13.75%)
         occurrences all number
    10
    35
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    47 / 159 (29.56%)
    48 / 160 (30.00%)
         occurrences all number
    64
    60
    Dysphonia
         subjects affected / exposed
    5 / 159 (3.14%)
    10 / 160 (6.25%)
         occurrences all number
    5
    10
    Dyspnoea
         subjects affected / exposed
    26 / 159 (16.35%)
    34 / 160 (21.25%)
         occurrences all number
    31
    46
    Epistaxis
         subjects affected / exposed
    14 / 159 (8.81%)
    30 / 160 (18.75%)
         occurrences all number
    16
    39
    Haemoptysis
         subjects affected / exposed
    9 / 159 (5.66%)
    5 / 160 (3.13%)
         occurrences all number
    10
    8
    Nasal dryness
         subjects affected / exposed
    0 / 159 (0.00%)
    12 / 160 (7.50%)
         occurrences all number
    0
    12
    Nasal inflammation
         subjects affected / exposed
    1 / 159 (0.63%)
    11 / 160 (6.88%)
         occurrences all number
    1
    13
    Oropharyngeal pain
         subjects affected / exposed
    10 / 159 (6.29%)
    7 / 160 (4.38%)
         occurrences all number
    11
    13
    Productive cough
         subjects affected / exposed
    11 / 159 (6.92%)
    6 / 160 (3.75%)
         occurrences all number
    13
    17
    Rhinorrhoea
         subjects affected / exposed
    12 / 159 (7.55%)
    24 / 160 (15.00%)
         occurrences all number
    17
    33
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 159 (5.66%)
    13 / 160 (8.13%)
         occurrences all number
    11
    16
    Anxiety
         subjects affected / exposed
    8 / 159 (5.03%)
    4 / 160 (2.50%)
         occurrences all number
    8
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    44 / 159 (27.67%)
    19 / 160 (11.88%)
         occurrences all number
    70
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    38 / 159 (23.90%)
    15 / 160 (9.38%)
         occurrences all number
    57
    19
    Weight decreased
         subjects affected / exposed
    9 / 159 (5.66%)
    18 / 160 (11.25%)
         occurrences all number
    11
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 159 (11.32%)
    12 / 160 (7.50%)
         occurrences all number
    22
    19
    Headache
         subjects affected / exposed
    22 / 159 (13.84%)
    14 / 160 (8.75%)
         occurrences all number
    30
    21
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 159 (3.14%)
    14 / 160 (8.75%)
         occurrences all number
    6
    16
    Eye disorders
    Dry eye
         subjects affected / exposed
    13 / 159 (8.18%)
    15 / 160 (9.38%)
         occurrences all number
    14
    16
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 159 (6.92%)
    14 / 160 (8.75%)
         occurrences all number
    12
    16
    Abdominal pain upper
         subjects affected / exposed
    17 / 159 (10.69%)
    17 / 160 (10.63%)
         occurrences all number
    18
    26
    Constipation
         subjects affected / exposed
    24 / 159 (15.09%)
    29 / 160 (18.13%)
         occurrences all number
    28
    33
    Diarrhoea
         subjects affected / exposed
    102 / 159 (64.15%)
    143 / 160 (89.38%)
         occurrences all number
    237
    451
    Dry mouth
         subjects affected / exposed
    14 / 159 (8.81%)
    11 / 160 (6.88%)
         occurrences all number
    14
    11
    Dyspepsia
         subjects affected / exposed
    14 / 159 (8.81%)
    16 / 160 (10.00%)
         occurrences all number
    19
    24
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 159 (8.18%)
    6 / 160 (3.75%)
         occurrences all number
    13
    7
    Mouth ulceration
         subjects affected / exposed
    7 / 159 (4.40%)
    20 / 160 (12.50%)
         occurrences all number
    7
    22
    Nausea
         subjects affected / exposed
    45 / 159 (28.30%)
    43 / 160 (26.88%)
         occurrences all number
    55
    69
    Stomatitis
         subjects affected / exposed
    18 / 159 (11.32%)
    63 / 160 (39.38%)
         occurrences all number
    25
    106
    Vomiting
         subjects affected / exposed
    19 / 159 (11.95%)
    31 / 160 (19.38%)
         occurrences all number
    22
    37
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    17 / 159 (10.69%)
    5 / 160 (3.13%)
         occurrences all number
    23
    7
    Alopecia
         subjects affected / exposed
    27 / 159 (16.98%)
    19 / 160 (11.88%)
         occurrences all number
    28
    19
    Dermatitis acneiform
         subjects affected / exposed
    34 / 159 (21.38%)
    34 / 160 (21.25%)
         occurrences all number
    45
    43
    Dry skin
         subjects affected / exposed
    63 / 159 (39.62%)
    52 / 160 (32.50%)
         occurrences all number
    72
    61
    Erythema
         subjects affected / exposed
    4 / 159 (2.52%)
    10 / 160 (6.25%)
         occurrences all number
    5
    12
    Nail disorder
         subjects affected / exposed
    3 / 159 (1.89%)
    10 / 160 (6.25%)
         occurrences all number
    3
    10
    Pruritus
         subjects affected / exposed
    40 / 159 (25.16%)
    40 / 160 (25.00%)
         occurrences all number
    67
    54
    Rash
         subjects affected / exposed
    87 / 159 (54.72%)
    100 / 160 (62.50%)
         occurrences all number
    139
    187
    Skin fissures
         subjects affected / exposed
    6 / 159 (3.77%)
    23 / 160 (14.38%)
         occurrences all number
    7
    26
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    9 / 159 (5.66%)
    7 / 160 (4.38%)
         occurrences all number
    9
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 159 (10.06%)
    11 / 160 (6.88%)
         occurrences all number
    21
    12
    Back pain
         subjects affected / exposed
    32 / 159 (20.13%)
    22 / 160 (13.75%)
         occurrences all number
    45
    25
    Muscle spasms
         subjects affected / exposed
    12 / 159 (7.55%)
    13 / 160 (8.13%)
         occurrences all number
    13
    15
    Musculoskeletal chest pain
         subjects affected / exposed
    13 / 159 (8.18%)
    9 / 160 (5.63%)
         occurrences all number
    20
    11
    Musculoskeletal pain
         subjects affected / exposed
    17 / 159 (10.69%)
    14 / 160 (8.75%)
         occurrences all number
    20
    16
    Neck pain
         subjects affected / exposed
    12 / 159 (7.55%)
    3 / 160 (1.88%)
         occurrences all number
    12
    3
    Pain in extremity
         subjects affected / exposed
    10 / 159 (6.29%)
    20 / 160 (12.50%)
         occurrences all number
    15
    21
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    10 / 159 (6.29%)
    14 / 160 (8.75%)
         occurrences all number
    12
    18
    Folliculitis
         subjects affected / exposed
    4 / 159 (2.52%)
    10 / 160 (6.25%)
         occurrences all number
    4
    14
    Nasopharyngitis
         subjects affected / exposed
    11 / 159 (6.92%)
    11 / 160 (6.88%)
         occurrences all number
    14
    14
    Paronychia
         subjects affected / exposed
    28 / 159 (17.61%)
    89 / 160 (55.63%)
         occurrences all number
    34
    136
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 159 (12.58%)
    16 / 160 (10.00%)
         occurrences all number
    27
    24
    Urinary tract infection
         subjects affected / exposed
    9 / 159 (5.66%)
    18 / 160 (11.25%)
         occurrences all number
    9
    25
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    39 / 159 (24.53%)
    45 / 160 (28.13%)
         occurrences all number
    49
    69
    Hypokalaemia
         subjects affected / exposed
    7 / 159 (4.40%)
    15 / 160 (9.38%)
         occurrences all number
    11
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2011
    The amendment introduced a change to the flow chart, for clarification of the informed consent process. Further major changes were the implementation of a new adverse event reporting process according to corporate Standard Operation Procedures of the sponsor, addition that afatinib is to be taken without food, and clarification on the archiving of tumour images.
    11 Sep 2012
    The amendment introduced changes to the flow chart to clarify time windows for certain procedures. The latest guidance on concomitant use of P-glycoprotein inhibitors and inducers in studies investigating afatinib was added. Further major additions concerned the management of the adverse events (AEs) diarrhoea, interstitial lung disease, and mucositis; drug induced liver injury monitoring; and reporting of sponsor-defined 'always serious AEs'. The afatinib dispersion method was changed, and reporting of progressive disease (PD) without signs or symptoms of PD was corrected.
    06 Mar 2013
    With this amendment, the text for the trial objectives was revised to have a clear distinction between end points and objectives. Regions were added to the competitive recruitment strategy, i.e. screening was competitive within two regions (Asian versus non-Asian countries), to ensure balanced ethnic composition of the trial population. With the introduction of this requirement, the sample size needed to be increased to 316 patients. The statistical section of the clinical trial protocol was revised to implement these changes; this included further details on statistical tests. A two-sided nominal alpha-level of 0.05 was prespecified for all statistical tests. Overall survival and ‘time to treatment failure’ changed from secondary to primary end points. The change was made to distinguish the end points considered to be of most clinical importance from the other, less important secondary end points. The time point for the primary progression-free survival (PFS) analysis readout was set as the time when at least 250 PFS events have accrued. Central imaging was added to the evaluation of tumour response. Further modifications were an amendment of the definition for end of trial, the introduction section on continued access to study treatment after study completion, and the introduction of paragraph on the management of keratitis. The reporting rules for progressive disease as an adverse event were changed.
    29 Jul 2015
    As it was estimated that overall survival (OS) data would be immature at the primary analysis time point, an additional time point for the analysis of mature OS data was defined. This time point was defined as the time when approximately two thirds of OS events (213 events) have occurred, and patients still alive and being followed up for OS have been so for at least 32 months from the date of randomisation.
    20 Jul 2017
    For patients continuing in the study, the frequency of imaging assessments was reduced after overall survival (OS) analysis. Assessments were now to be performed every 18 weeks. More frequent assessments were no longer required as patients had been on treatment for more than 3 years. Central independent review of tumour imaging was stopped after database lock for the analysis of OS. As sufficient data had been collected for the primary analysis and additional OS analysis, the definition of end of trial was changed to allow earlier completion of the trial. The frequency of electrocardiogram assessments and echocardiogram/multiple-gated acquisition scans was changed to “as clinically indicated”. Completion of Quality of Life questionnaires was no longer requested after database lock for the analysis of OS as sufficient data had been collected.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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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