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    Clinical Trial Results:
    LUX-Lung 3; A randomised, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR-activating mutation

    Summary
    EudraCT number
    2008-005615-18
    Trial protocol
    IE   FR   GB   BE   AT   DE   HU   IT  
    Global end of trial date
    17 Mar 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Nov 2021
    First version publication date
    24 Mar 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.32
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00949650
    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, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 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
    07 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Feb 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy and safety of Afatinib monotherapy with Pemetrexed/Cisplatin chemotherapy as first-line treatment in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)-naïve patients with stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or IV adenocarcinoma of the lung harbouring an EGFR mutation.
    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. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    -
    Evidence for comparator
    The comparator treatment was Pemetrexed/Cisplatin Chemotherapy.
    Actual start date of recruitment
    17 Aug 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    86 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 64
    Country: Number of subjects enrolled
    Brazil: 26
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    Chile: 21
    Country: Number of subjects enrolled
    Hong Kong: 11
    Country: Number of subjects enrolled
    Argentina: 28
    Country: Number of subjects enrolled
    Japan: 185
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 57
    Country: Number of subjects enrolled
    Malaysia: 55
    Country: Number of subjects enrolled
    Peru: 26
    Country: Number of subjects enrolled
    Philippines: 40
    Country: Number of subjects enrolled
    Russian Federation: 78
    Country: Number of subjects enrolled
    Taiwan: 129
    Country: Number of subjects enrolled
    Thailand: 147
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 39
    Country: Number of subjects enrolled
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 45
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    Germany: 71
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Ireland: 32
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    United Kingdom: 32
    Worldwide total number of subjects
    1269
    EEA total number of subjects
    261
    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)
    779
    From 65 to 84 years
    485
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    Two-arm, randomised (2:1 ratio), open-label, active-controlled, parallel-group comparison. 345 patients were randomised, 5 patients were not treated: 4 patients were not eligible for treatment and 1 patient in the chemotherapy arm refused to take study medication.

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific 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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Afatinib 40 mg
    Arm description
    Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.
    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
    Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.

    Arm title
    Pemetrexed/Cisplatin Chemotherapy
    Arm description
    Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients received Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.

    Number of subjects in period 1 [1]
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Started
    230
    115
    Completed
    0
    0
    Not completed
    230
    115
         Other Adverse Event [AE]
    28
    17
         Completed 6 courses of chemotherapy
    -
    60
         Refusal to continue medication
    7
    11
         Other not specified above
    5
    -
         Progressive disease
    188
    19
         Protocol deviation
    1
    4
         Not treated
    1
    4
    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 1269 enrolled subjects only 345 were treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    -

    Reporting group values
    Overall Study Total
    Number of subjects
    345
    Age categorical
    Units: Subjects
    Age Continuous
    Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    Units: years
        arithmetic mean (standard deviation)
    60.3 ± 10.1 -
    Gender, Male/Female
    Units: Subjects
        Female
    224 224
        Male
    121 121
    Race/Ethnicity, Customized
    Race (Asian/non-Asian) was a stratification factor.
    Units: Subjects
        Asian
    249 249
        Non-Asian
    96 96
    Epidermal Growth Factor Receptor (EGFR) mutation group
    EGFR mutation group (L858R/Deletion Exon 19/Other) was a stratification factor.
    Units: Subjects
        EGFR mutation category: L858R
    138 138
        EGFR mutation category: Deletion Exon 19
    169 169
        EGFR mutation category: Other
    38 38
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    ECOG PS measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. 1=Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. 2=Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. 3=Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. 4=Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 5=Dead.
    Units: Subjects
        ECOG PS 0 (baseline)
    133 133
        ECOG PS 1 (baseline)
    211 211
        ECOG PS 2 (baseline)
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Afatinib 40 mg
    Reporting group description
    Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.

    Reporting group title
    Pemetrexed/Cisplatin Chemotherapy
    Reporting group description
    Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.

    Subject analysis set title
    Afatinib 20 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients receiving Afatinib monotherapy 20 mg once daily (q.d.)

    Subject analysis set title
    Afatinib 30 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients receiving Afatinib monotherapy 30 mg once daily (q.d.)

    Subject analysis set title
    Afatinib 50 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients receiving Afatinib monotherapy 50 mg once daily (q.d.)

    Primary: Progression-Free Survival (PFS) Time

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    End point title
    Progression-Free Survival (PFS) Time
    End point description
    PFS was defined as time from randomisation to disease progression or death whichever occured first. Assessed by central independent review according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Median time results from unstratified Kaplan-Meier estimates. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Primary
    End point timeframe
    Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [1]
    115 [2]
    Units: Months.
        median (confidence interval 95%)
    11.17 (9.63 to 13.70)
    6.90 (5.39 to 8.25)
    Notes
    [1] - RS.
    [2] - RS.
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Pemetrexed/Cisplatin Chemotherapy v Afatinib 40 mg
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0002 [3]
    Method
    Logrank
    Confidence interval
    Notes
    [3] - Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Cox Proportional Hazard (PH) regression stratified by epidermal growth factor receptor (EGFR) mutation group and race. Hazard Ratio (HR) was calculated as Afatinib 40 mg versus Pemetrexed/Cisplatin Chemotherapy.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0002
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.576
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.426
         upper limit
    0.778

    Secondary: Percentage of Patients with Objective Response (OR)

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    End point title
    Percentage of Patients with Objective Response (OR)
    End point description
    OR was defined as Complete Response (CR) or Partial Response (PR). Assessed by central independent review according to RECIST 1.1. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [4]
    115 [5]
    Units: Percentage of patients with OR.
        number (confidence interval 95%)
    56.5 (49.8 to 63.0)
    22.6 (15.3 to 31.3)
    Notes
    [4] - RS.
    [5] - RS.
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Logistic regression stratified for EGFR mutation group and race. Odds Ratio (OR) was calculated as Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.802
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.855
         upper limit
    8.075

    Secondary: Percentage of Participants with Disease Control (DC)

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    End point title
    Percentage of Participants with Disease Control (DC)
    End point description
    DC was defined as a patient with OR or Stable Disease (SD). Assessed by central independent review according to the RECIST 1.1. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [6]
    115 [7]
    Units: Percentage of participants with DC.
        number (confidence interval 95%)
    90.4 (85.9 to 93.9)
    80.9 (72.5 to 87.6)
    Notes
    [6] - RS.
    [7] - RS.
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Logistic regression stratified for EGFR mutation group and race. OR was calculated as Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0118
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.288
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.202
         upper limit
    4.356

    Secondary: Overall Survival (OS) Time

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    End point title
    Overall Survival (OS) Time
    End point description
    OS was defined as time from randomisation to death. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    From randomisation to cut-off date (17MAR2017).
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [8]
    115 [9]
    Units: Months.
        median (confidence interval 95%)
    28.16 (24.64 to 33.58)
    28.22 (20.73 to 33.22)
    Notes
    [8] - RS.
    [9] - RS.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Cox PH regression stratified by EGFR mutation group and race.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.385
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.66
         upper limit
    1.174
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.7916 [10]
    Method
    Logrank
    Confidence interval
    Notes
    [10] - Two-sided p-value from log-rank test stratified by EGFR mutation group and race.

    Secondary: Tumour Shrinkage

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    End point title
    Tumour Shrinkage
    End point description
    Tumour shrinkage was calculated as the minimum Sum of Diameters (SoD) of target lesions from all post-baseline tumour assessments, as read by the central independent review. The mean of these minimum values were presented after adjusting for baseline SoD, EGFR mutation group and race. RS. There were only 203 patients in the Afatinib 40 mg arm and 101 patients in the Pemetrexed/Cisplatin Chemotherapy with tumour measurements.
    End point type
    Secondary
    End point timeframe
    Tumour assessments were performed at Screening, Week 6, Week 12, Week 18 and then every 12-18 weeks until disease progression
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    203 [11]
    101 [12]
    Units: mm.
        arithmetic mean (standard error)
    33.19 ± 1.12
    43.00 ± 1.59
    Notes
    [11] - RS.
    [12] - RS.
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Adjusted for baseline SoD, EGFR mutation group and race. Mean Difference (Final Values) was calculated as Afatinib 40 mg-Pemetrexed/Cisplatin Chemotherapy.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -9.82
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.64
         upper limit
    -5.99

    Secondary: Change from Baseline in Body Weight

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    End point title
    Change from Baseline in Body Weight
    End point description
    Because the PFS was longer for patients in the Afatinib arm than for patients in the chemotherapy arm, the period of data collection for ECOG status and body weight continued for a longer time in the Afatinib arm. RS. Only patients with baseline and at least one post-baseline assessment were included.
    End point type
    Secondary
    End point timeframe
    Baseline and throughout the trial until progression (every 3 weeks), up to 28 months.
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    224 [13]
    109 [14]
    Units: Kg.
    arithmetic mean (standard deviation)
        Change from baseline at lowest value
    -3.95 ± 3.91
    -2.68 ± 2.90
        Change from baseline at last value
    -1.19 ± 5.36
    -0.29 ± 4.02
    Notes
    [13] - RS.
    [14] - RS.
    No statistical analyses for this end point

    Secondary: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)

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    End point title
    Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
    End point description
    ECOG PS measured on 6 point scale to assess participant’s performance status. 0=Fully active, able to carry on all pre-disease activities without restriction. 1=Restricted in physically strenuous activity, but ambulatory and able to carry out light or sedentary work. 2=Ambulatory (>50 percent of waking hours), capable of all self-care, unable to carry out any work activities. 3=Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours. 4=Completely disabled, cannot carry on any self-care, totally confined to bed or chair. 5=Dead. RS. Only patients with baseline and at least one post-baseline assessment were included.
    End point type
    Secondary
    End point timeframe
    Throughout the trial until progression (every 3 weeks), up to 28 months.
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    228 [15]
    111 [16]
    Units: Participants
        ECOG PS 0 (last value)
    92
    41
        ECOG PS 1 (last value)
    138
    73
        ECOG PS 2 (last value)
    0
    1
    Notes
    [15] - RS.
    [16] - RS.
    No statistical analyses for this end point

    Secondary: Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing

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    End point title
    Health Related Quality of Life (HRQOL): Time to Deterioration in Coughing
    End point description
    HRQOL was measured by European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire C30 (QLQ-C30) and its lung cancer specific module LC13 (QLQ-LC13). Analysis for cough is based on QLQ-LC13 question 1. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. Afatinib 40 mg [99999]: As only 82 patients (35.7 percent) in the Afatinib 40 mg deteriorated, the upper limit of CI was not estimable. Pemetrexed/Cisplatin Chemotherapy [99999]: As only 44 patients (38.3 percent) in the Pemetrexed/Cisplatin Chemotherapy deteriorated, the upper limit of the CI was not estimable. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    Throughout the trial until progression (every 3 weeks).
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [17]
    115 [18]
    Units: Months.
        median (confidence interval 95%)
    26.97 (19.22 to 99999)
    8.02 (4.44 to 99999)
    Notes
    [17] - RS.
    [18] - RS.
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0062 [19]
    Method
    Logrank
    Confidence interval
    Notes
    [19] - Two-sided p-value from log-rank test stratified by EGFR mutation group and race.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Cox PH regression stratified by EGFR mutation group and race. HR was calculated as Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.2133
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.589
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.401
         upper limit
    0.866

    Secondary: HRQOL: Time to Deterioration in Dyspnoea

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    End point title
    HRQOL: Time to Deterioration in Dyspnoea
    End point description
    HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for dyspnoea is based on composite of QLQ-LC13 questions 3-5. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    Throughout the trial until progression (every 3 weeks).
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [20]
    115 [21]
    Units: Months.
        median (confidence interval 95%)
    10.41 (5.59 to 15.93)
    2.86 (2.17 to 4.90)
    Notes
    [20] - RS.
    [21] - RS.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Cox PH regression stratified by EGFR mutation group and race. HR was calculated as Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0078
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.499
         upper limit
    0.927
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0129 [22]
    Method
    Logrank
    Confidence interval
    Notes
    [22] - Two-sided p-value from log-rank test stratified by EGFR mutation group and race.

    Secondary: HRQOL: Time to Deterioration in Pain

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    End point title
    HRQOL: Time to Deterioration in Pain
    End point description
    HRQOL was measured by EORTC QLQ-C30 and its lung cancer specific module QLQ-LC13. Analysis for pain is based on composite of QLQ-C30 questions 9 and 19. Time to deterioration was defined as the time from randomisation to a score increased (worsened) by at least 10 points from baseline (0-100 point scale). Patients were considered deteriorated at time of death. Median time results from unstratified Kaplan-Meier estimates. Randomised Set (RS): The randomised set includes all patients who were randomised to receive treatment, whether treated or not.
    End point type
    Secondary
    End point timeframe
    Throughout the trial until progression (every 3 weeks).
    End point values
    Afatinib 40 mg Pemetrexed/Cisplatin Chemotherapy
    Number of subjects analysed
    230 [23]
    115 [24]
    Units: Months.
        median (confidence interval 95%)
    4.17 (2.79 to 5.59)
    3.09 (2.17 to 3.98)
    Notes
    [23] - RS.
    [24] - RS.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Cox PH regression stratified by EGFR mutation group and race. HR was calculated as Afatinib 40 mg vs. Pemetrexed/Cisplatin Chemotherapy, if HR<1 then favours Afatinib 40 mg.
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0427
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.826
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.618
         upper limit
    1.104
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Afatinib 40 mg v Pemetrexed/Cisplatin Chemotherapy
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1882 [25]
    Method
    Logrank
    Confidence interval
    Notes
    [25] - Two-sided p-value from log-rank test stratified by EGFR mutation group and race.

    Secondary: Trough Plasma Concentrations of Afatinib at Day 22

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    End point title
    Trough Plasma Concentrations of Afatinib at Day 22 [26]
    End point description
    Trough plasma concentrations of Afatinib at Day 22 (course 2, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. Patients from the treated set (The treated set included all randomised patients who were documented to have taken at least 1 dose of study medication (i.e. Afatinib or Pemetrexed / Cisplatin)) with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
    End point type
    Secondary
    End point timeframe
    Day 22.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was defined only for the group "Aftainib 40mg".
    End point values
    Afatinib 40 mg Afatinib 20 mg Afatinib 30 mg Afatinib 50 mg
    Number of subjects analysed
    165 [27]
    0 [28]
    11 [29]
    3 [30]
    Units: ng/mL.
        geometric mean (geometric coefficient of variation)
    28.0 ± 85.0
    ±
    21.8 ± 36.6
    29.9 ± 46.1
    Notes
    [27] - TS.
    [28] - TS. No subjets analysed.
    [29] - TS.
    [30] - TS.
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentrations of Afatinib at Day 29

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    End point title
    Trough Plasma Concentrations of Afatinib at Day 29 [31]
    End point description
    Trough plasma concentrations of Afatinib at day 29 (course 2, visit 2) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. Patients from the treated set (The treated set included all randomised patients who were documented to have taken at least 1 dose of study medication (i.e. Afatinib or Pemetrexed / Cisplatin)) with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
    End point type
    Secondary
    End point timeframe
    Day 29.
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was defined only for the group "Aftainib 40mg".
    End point values
    Afatinib 40 mg Afatinib 20 mg Afatinib 30 mg Afatinib 50 mg
    Number of subjects analysed
    143 [32]
    0 [33]
    25 [34]
    16 [35]
    Units: ng/mL.
        geometric mean (geometric coefficient of variation)
    25.8 ± 69.5
    ±
    28.0 ± 82.4
    29.6 ± 79.2
    Notes
    [32] - TS.
    [33] - TS. No subjects analysed.
    [34] - TS.
    [35] - TS.
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentrations of Afatinib at Day 43

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    End point title
    Trough Plasma Concentrations of Afatinib at Day 43 [36]
    End point description
    Trough plasma concentrations of Afatinib at Day 43 (course 3, visit 1) after multiple daily dosing of 40 mg Afatinib and after dose escalation to 50 mg or dose reduction to 30 mg or 20 mg. Patients from the treated set (The treated set included all randomised patients who were documented to have taken at least 1 dose of study medication (i.e. Afatinib or Pemetrexed / Cisplatin)) with evaluable data and who had at least 1 valid Afatinib plasma concentration available on this time point.
    End point type
    Secondary
    End point timeframe
    Day 43.
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was defined only for the group "Aftainib 40mg".
    End point values
    Afatinib 40 mg Afatinib 20 mg Afatinib 30 mg Afatinib 50 mg
    Number of subjects analysed
    126 [37]
    2 [38]
    39 [39]
    14 [40]
    Units: ng/mL.
        geometric mean (geometric coefficient of variation)
    23.5 ± 66.2
    24.4 ± 260
    24.7 ± 63.9
    27.5 ± 64.4
    Notes
    [37] - TS.
    [38] - TS.
    [39] - TS.
    [40] - TS.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Afatinib 40
    Reporting group description
    Patients received Afatinib monotherapy 40 mg film-coated tablets orally once daily.

    Reporting group title
    Pe500+Cis75
    Reporting group description
    Patients received Pemetrexed 500 mg/m^2 lyophilised powder as intravenous infusion after Cisplatin 75 mg/m^2 solution for infusion as intravenous infusion on Day 1 of each 21-day treatment course up to 6 cycles.

    Serious adverse events
    Afatinib 40 Pe500+Cis75
    Total subjects affected by serious adverse events
         subjects affected / exposed
    72 / 229 (31.44%)
    25 / 111 (22.52%)
         number of deaths (all causes)
    193
    88
         number of deaths resulting from adverse events
    15
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    3 / 229 (1.31%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    3 / 229 (1.31%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (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
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Abasia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 229 (0.44%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Disease progression
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Fatigue
         subjects affected / exposed
    3 / 229 (1.31%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 229 (1.75%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Epistaxis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 229 (0.87%)
    3 / 111 (2.70%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 229 (0.87%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 229 (1.31%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Schizophreniform disorder
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood sodium decreased
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (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
    Depressed level of consciousness
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (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
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 229 (1.31%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    15 / 229 (6.55%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    15 / 15
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 229 (0.00%)
    2 / 111 (1.80%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    11 / 229 (4.80%)
    3 / 111 (2.70%)
         occurrences causally related to treatment / all
    9 / 13
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 229 (0.44%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningoencephalitis herpetic
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 229 (1.75%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 229 (1.31%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes with hyperosmolarity
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    4 / 229 (1.75%)
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 111 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Afatinib 40 Pe500+Cis75
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    229 / 229 (100.00%)
    108 / 111 (97.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 229 (6.11%)
    14 / 111 (12.61%)
         occurrences all number
    14
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 229 (6.99%)
    14 / 111 (12.61%)
         occurrences all number
    21
    17
    Chest pain
         subjects affected / exposed
    16 / 229 (6.99%)
    14 / 111 (12.61%)
         occurrences all number
    19
    15
    Fatigue
         subjects affected / exposed
    45 / 229 (19.65%)
    39 / 111 (35.14%)
         occurrences all number
    55
    59
    Malaise
         subjects affected / exposed
    7 / 229 (3.06%)
    6 / 111 (5.41%)
         occurrences all number
    7
    6
    Mucosal inflammation
         subjects affected / exposed
    67 / 229 (29.26%)
    5 / 111 (4.50%)
         occurrences all number
    110
    6
    Oedema
         subjects affected / exposed
    7 / 229 (3.06%)
    13 / 111 (11.71%)
         occurrences all number
    8
    27
    Oedema peripheral
         subjects affected / exposed
    17 / 229 (7.42%)
    8 / 111 (7.21%)
         occurrences all number
    17
    10
    Pyrexia
         subjects affected / exposed
    28 / 229 (12.23%)
    6 / 111 (5.41%)
         occurrences all number
    34
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 229 (17.03%)
    21 / 111 (18.92%)
         occurrences all number
    54
    23
    Dyspnoea
         subjects affected / exposed
    18 / 229 (7.86%)
    12 / 111 (10.81%)
         occurrences all number
    19
    13
    Epistaxis
         subjects affected / exposed
    41 / 229 (17.90%)
    1 / 111 (0.90%)
         occurrences all number
    52
    1
    Hiccups
         subjects affected / exposed
    5 / 229 (2.18%)
    10 / 111 (9.01%)
         occurrences all number
    5
    21
    Nasal inflammation
         subjects affected / exposed
    15 / 229 (6.55%)
    0 / 111 (0.00%)
         occurrences all number
    16
    0
    Oropharyngeal pain
         subjects affected / exposed
    13 / 229 (5.68%)
    3 / 111 (2.70%)
         occurrences all number
    17
    3
    Rhinorrhoea
         subjects affected / exposed
    16 / 229 (6.99%)
    7 / 111 (6.31%)
         occurrences all number
    21
    9
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    37 / 229 (16.16%)
    10 / 111 (9.01%)
         occurrences all number
    53
    10
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    27 / 229 (11.79%)
    3 / 111 (2.70%)
         occurrences all number
    43
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 229 (9.61%)
    1 / 111 (0.90%)
         occurrences all number
    32
    3
    Blood creatinine increased
         subjects affected / exposed
    5 / 229 (2.18%)
    10 / 111 (9.01%)
         occurrences all number
    6
    16
    Haemoglobin decreased
         subjects affected / exposed
    3 / 229 (1.31%)
    13 / 111 (11.71%)
         occurrences all number
    7
    20
    Neutrophil count decreased
         subjects affected / exposed
    1 / 229 (0.44%)
    8 / 111 (7.21%)
         occurrences all number
    3
    19
    Weight decreased
         subjects affected / exposed
    44 / 229 (19.21%)
    16 / 111 (14.41%)
         occurrences all number
    59
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    28 / 229 (12.23%)
    12 / 111 (10.81%)
         occurrences all number
    36
    16
    Dysgeusia
         subjects affected / exposed
    18 / 229 (7.86%)
    9 / 111 (8.11%)
         occurrences all number
    20
    9
    Headache
         subjects affected / exposed
    37 / 229 (16.16%)
    19 / 111 (17.12%)
         occurrences all number
    55
    25
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    19 / 229 (8.30%)
    29 / 111 (26.13%)
         occurrences all number
    24
    30
    Leukopenia
         subjects affected / exposed
    6 / 229 (2.62%)
    21 / 111 (18.92%)
         occurrences all number
    6
    53
    Neutropenia
         subjects affected / exposed
    4 / 229 (1.75%)
    35 / 111 (31.53%)
         occurrences all number
    4
    86
    Thrombocytopenia
         subjects affected / exposed
    1 / 229 (0.44%)
    8 / 111 (7.21%)
         occurrences all number
    1
    21
    Eye disorders
    Dry eye
         subjects affected / exposed
    14 / 229 (6.11%)
    0 / 111 (0.00%)
         occurrences all number
    14
    0
    Vision blurred
         subjects affected / exposed
    12 / 229 (5.24%)
    2 / 111 (1.80%)
         occurrences all number
    12
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 229 (5.68%)
    5 / 111 (4.50%)
         occurrences all number
    17
    5
    Abdominal pain upper
         subjects affected / exposed
    15 / 229 (6.55%)
    8 / 111 (7.21%)
         occurrences all number
    25
    9
    Cheilitis
         subjects affected / exposed
    22 / 229 (9.61%)
    0 / 111 (0.00%)
         occurrences all number
    27
    0
    Constipation
         subjects affected / exposed
    37 / 229 (16.16%)
    39 / 111 (35.14%)
         occurrences all number
    44
    54
    Diarrhoea
         subjects affected / exposed
    216 / 229 (94.32%)
    25 / 111 (22.52%)
         occurrences all number
    535
    31
    Dyspepsia
         subjects affected / exposed
    21 / 229 (9.17%)
    7 / 111 (6.31%)
         occurrences all number
    25
    10
    Mouth ulceration
         subjects affected / exposed
    24 / 229 (10.48%)
    3 / 111 (2.70%)
         occurrences all number
    36
    3
    Nausea
         subjects affected / exposed
    65 / 229 (28.38%)
    75 / 111 (67.57%)
         occurrences all number
    98
    174
    Stomatitis
         subjects affected / exposed
    88 / 229 (38.43%)
    10 / 111 (9.01%)
         occurrences all number
    144
    13
    Vomiting
         subjects affected / exposed
    53 / 229 (23.14%)
    50 / 111 (45.05%)
         occurrences all number
    79
    83
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    52 / 229 (22.71%)
    0 / 111 (0.00%)
         occurrences all number
    67
    0
    Alopecia
         subjects affected / exposed
    30 / 229 (13.10%)
    20 / 111 (18.02%)
         occurrences all number
    33
    20
    Dermatitis acneiform
         subjects affected / exposed
    32 / 229 (13.97%)
    0 / 111 (0.00%)
         occurrences all number
    47
    0
    Dry skin
         subjects affected / exposed
    72 / 229 (31.44%)
    2 / 111 (1.80%)
         occurrences all number
    85
    2
    Nail disorder
         subjects affected / exposed
    14 / 229 (6.11%)
    0 / 111 (0.00%)
         occurrences all number
    14
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    19 / 229 (8.30%)
    0 / 111 (0.00%)
         occurrences all number
    44
    0
    Pruritus
         subjects affected / exposed
    50 / 229 (21.83%)
    1 / 111 (0.90%)
         occurrences all number
    66
    1
    Rash
         subjects affected / exposed
    145 / 229 (63.32%)
    11 / 111 (9.91%)
         occurrences all number
    243
    12
    Skin exfoliation
         subjects affected / exposed
    13 / 229 (5.68%)
    0 / 111 (0.00%)
         occurrences all number
    14
    0
    Skin fissures
         subjects affected / exposed
    16 / 229 (6.99%)
    0 / 111 (0.00%)
         occurrences all number
    20
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 229 (9.17%)
    6 / 111 (5.41%)
         occurrences all number
    27
    6
    Back pain
         subjects affected / exposed
    37 / 229 (16.16%)
    13 / 111 (11.71%)
         occurrences all number
    44
    13
    Muscle spasms
         subjects affected / exposed
    20 / 229 (8.73%)
    0 / 111 (0.00%)
         occurrences all number
    22
    0
    Musculoskeletal pain
         subjects affected / exposed
    21 / 229 (9.17%)
    2 / 111 (1.80%)
         occurrences all number
    24
    2
    Myalgia
         subjects affected / exposed
    12 / 229 (5.24%)
    1 / 111 (0.90%)
         occurrences all number
    18
    1
    Pain in extremity
         subjects affected / exposed
    20 / 229 (8.73%)
    4 / 111 (3.60%)
         occurrences all number
    24
    5
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    28 / 229 (12.23%)
    3 / 111 (2.70%)
         occurrences all number
    35
    3
    Cystitis
         subjects affected / exposed
    15 / 229 (6.55%)
    1 / 111 (0.90%)
         occurrences all number
    18
    1
    Folliculitis
         subjects affected / exposed
    12 / 229 (5.24%)
    0 / 111 (0.00%)
         occurrences all number
    12
    0
    Nasopharyngitis
         subjects affected / exposed
    39 / 229 (17.03%)
    9 / 111 (8.11%)
         occurrences all number
    67
    9
    Paronychia
         subjects affected / exposed
    132 / 229 (57.64%)
    0 / 111 (0.00%)
         occurrences all number
    188
    0
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 229 (12.66%)
    4 / 111 (3.60%)
         occurrences all number
    47
    5
    Urinary tract infection
         subjects affected / exposed
    19 / 229 (8.30%)
    5 / 111 (4.50%)
         occurrences all number
    26
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    70 / 229 (30.57%)
    61 / 111 (54.95%)
         occurrences all number
    96
    111
    Hypokalaemia
         subjects affected / exposed
    21 / 229 (9.17%)
    4 / 111 (3.60%)
         occurrences all number
    35
    8
    Hyponatraemia
         subjects affected / exposed
    4 / 229 (1.75%)
    6 / 111 (5.41%)
         occurrences all number
    4
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2010
    Exclusion criterion 21 was changed; it originally referred to patients randomised to treatment with chemotherapy only. As the consent process took place before randomisation, it was necessary to cover both treatment arms with this exclusion criterion. The restricted medications during treatment with Afatinib were changed. It was specified that the list of restricted medications refers to all patients randomised. An additional explanatory paragraph was added that the concomitant use of potent P-gp inhibitors and inducers was to be avoided during treatment with Afatinib. The background was that a trial [1200.79] in healthy volunteers indicated that co-administration of these drugs affected the pharmacokinetics of Afatinib.
    09 May 2011
    Several changes and corrections were introduced with the second amendment to the protocol; major changes are presented. It was specified that the trial had 2 screening visits. During the first screening visit, the patient signed the first informed consent and agreed to the EGFR mutation testing. During the second screening visit patients with positive EGFR mutation testing signed a second informed consent and agreed to participate in the main part of the trial. The strict time window for Afatinib intake was removed to accommodate individual patient’s daily schedule preference because Afatinib has a long half-life. The storage conditions for Afatinib were corrected to match the labelling in the USA and Canada. Tablets were to be stored at the temperature specified in the label [i.e. between 15°C and 30°C in the USA and Canada and not above 25ºC in all other countries]. It was specified how data in HRQOL questionnaires were to be handled for Adverse Event [AE] reporting. The length of the observation period of this trial was specified. The focus of the analysis of HRQOL was broadened to include all summary scales and items measuring cough, dyspnoea, and pain measured by the EORTC QLQ-C30 and QLQ-LC13 questionnaires. The time window of the on-treatment period was modified to match the planned safety analysis with other Afatinib trials. It was specified that the decision of whether to proceed to full accrual was based on the first 40 patients randomised to treatment with Afatinib whether or not they had stopped treatment before the Week 6 assessment. New information was added to the appendix of the protocol. The appendix was updated with the current Summary of Product Characteristics [SPC] of Cisplatin provided for the trial. In addition, the RECIST version 1.1 criteria in the appendix were updated to ensure consistency with the imaging charter for the central independent review of radiological imaging.
    01 Aug 2012
    The third amendment to the protocol introduced several changes; the key changes are presented. Amendment 3 changed the frequency of Electro Cardio Gram [ECG] assessments from once every third course to “as clinically indicated”. The amendment was released after at least 18 months of collection of centrally assessed ECG data for all randomised patients. The data showed that Afatinib did not have any effect on QTc or other ECG parameters; therefore routine monitoring of ECG was no longer required. The requirements for collection of biopsy and blood samples at the time of Progressive Disease [PD] were changed for both treatment arms. Based on the review of already collected data, further follow-up biopsy and blood samples were not requested. The frequency of collection of observation-period data was changed. A data snapshot could now be requested at any time; after the analysis of OS, the collection of observation-period data could be reduced in frequency or stopped, as decided by the Trial Clinical Monitor [TCM]. The requirement for reporting ‘always serious’ adverse events as per new corporate standard was added. The new corporate standard for monitoring and assessment of potential drug-induced liver injury was added. Based on the new clinical data, the recommendation to avoid the use of P-gp inhibitors or inducers in patients treated with Afatinib was modified to allow for their use with caution if clinically indicated.
    20 Sep 2013
    Several changes affecting patients still ongoing in the trial were introduced with the fourth amendment to the protocol; the main changes are presented. Routine monitoring of Left Ventricular Ejection Fraction [LVEF] was no longer required after database lock for the analysis of OS. LVEF assessments were now to be performed as clinically indicated. No safety signals indicating an effect of Afatinib on the cardiac contractility had been identified in this trial and using a larger safety database. Routine monitoring of LVEF was therefore no longer required. The frequency of trial visits was reduced after database lock for the analysis of OS. A treatment course now comprised 9 weeks [63 days] and FU visits were to be performed every 9 weeks [63 days] until PD or death. All patients had been on treatment for more than 2 years, therefore the frequency of clinic visits could be reduced. The frequency of imaging assessments was reduced after database lock for the analysis of OS. Assessments were now to be performed every 18 weeks. More frequent assessments were no longer required after assessment of the primary endpoint PFS. Central independent review of tumour imaging was stopped after database lock for the analysis of OS. Central independent review was no longer needed as the primary endpoint PFS had been assessed and reported. Completion of HRQOL questionnaires was no longer requested after database lock for the analysis of OS. Sufficient HRQOL data had been collected for the analysis. Patients could move onto an alternative supply of Afatinib after database lock for the analysis of OS, as Afatinib had been approved for use in patients with EGFR mutation positive Non-Small Cell Lung Cancer [NSCLC] in some countries by the time of the analysis. The follow-up and observation periods were amended to allow for completion of the trial. The follow-up period was to end on 31 Jan 2015 with the exception of FU visit 1 which was still required to assess Adverse Events [AEs].
    04 Dec 2014
    The follow-up and observation periods were amended to allow continued collection of data after 31 Jan 2015, until all patients had completed study treatment. Follow-up visit 1 was still required for all patients to assess for AEs.

    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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