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    Clinical Trial Results:
    A Randomized Phase 2 Trial of PF-00299804 Versus Erlotinib for the Treatment of Advanced Non-Small Cell Lung Cancer After Failure of at Least 1 Prior Chemotherapy Regimen

    Summary
    EudraCT number
    		 2008-005235-14
    Trial protocol
    		 ES   GB  
    Global end of trial date
    15 Aug 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Jun 2016
    First version publication date
    12 Aug 2015
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    reporting periods and duplicate AEs in their data

    Trial information

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    Trial identification
    Sponsor protocol code
    A7471028
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00769067
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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
    15 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was a Phase 2, open-label study to evaluate dacomitinib relative to erlotinib in the clinical setting for which erlotinib received approval for treatment of advanced Non Small Cell Lung Cancer (NSCLC) after failure of at least 1 prior chemotherapy regimen. In addition to the clinical safety and efficacy of dacomitinib, this study seeked to better understand the prognostic and predictive factors associated with advanced NSCLC, including both clinical factors (smoking, histology, sex, and race/ethnicity) and biomarkers (including epidermal growth factor receptor [EGFR], other human epidermal growth factor receptor [HER] family members, and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] genetic changes).
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants. The final protocol and any amendments were reviewed and approved by the Institutional Review Board(s) (IRB) and/or Independent Ethics Committee(s) (IEC) at each of the investigational centres participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2008
    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
    Australia: 16
    Country: Number of subjects enrolled
    Brazil: 25
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 15
    Worldwide total number of subjects
    187
    EEA total number of subjects
    62
    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)
    125
    From 65 to 84 years
    61
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened to ensure evidence of advanced non-small cell lung cancer (NSCLC), tumour tissue from either an original diagnostic biopsy or a recently obtained biopsy, left ventricular ejection fraction (LVEF) determination and satisfactory haematology, blood chemistry, coagulation and urine results within 7 days of start of treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Erlotinib
    Arm description
    		 Erlotinib 150 milligram (mg) tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg daily (at about the same time of each day) continuously in 28-day cycles until unacceptable toxicity, tumor progression or death.

    Arm title
    		 Dacomitinib
    Arm description
    		 Dacomitinib (PF-00299804) 45 mg tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dacomitinib
    Investigational medicinal product code
    Other name
    PF-00299804
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    45 mg daily (at about the same time of each day) continuously in 28-day cycles until unacceptable toxicity, tumor progression or death.

    Number of subjects in period 1
    		Erlotinib Dacomitinib
    Started
    94
    93
    Treated
    94
    93
    Completed
    0
    0
    Not completed
    94
    93
         Death
    89
    86
         Unspecified
    1
    3
         Study Terminated by Sponsor
    1
    3
         Lost to follow-up
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    		 Erlotinib 150 milligram (mg) tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.

    Reporting group title
    Dacomitinib
    Reporting group description
    		 Dacomitinib (PF-00299804) 45 mg tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.

    Reporting group values
    		 Erlotinib Dacomitinib Total
    Number of subjects
    		 94 93 187
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ± 11.96 59.9 ± 9.46 -
    Gender categorical
    Units: Subjects
        Female
    		 38 38 76
        Male
    		 56 55 111

    End points

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    End points reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    		 Erlotinib 150 milligram (mg) tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.

    Reporting group title
    Dacomitinib
    Reporting group description
    		 Dacomitinib (PF-00299804) 45 mg tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.

    Subject analysis set title
    Dacomitinib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Dacomitinib (PF-00299804) 45 mg tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumour progression or death.

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS) [1]
    End point description
    PFS: Time in weeks from randomization to date of objective disease progression or death due to any cause, whichever occurred first. PFS was calculated as (first event date or last known event-free date [if the event date unavailable] minus the date of randomization plus 1) divided by 7. Objective progression was defined using Response Evaluation Criteria in Solid Tumors (RECIST), as at least 20 percent (%) increase in the sum of longest dimensions (LDs) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The baseline period arm for dacomitinib includes only those subjects treated (i.e. the safety population). This outcome measure was analysed for all subjects randomised (i.e. the ITT population).
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    94 [2]
    94 [3]
    Units: Weeks
        median (confidence interval 95%)
    8.3 (7.9 to 11.7)
    12.4 (8.1 to 16.1)
    Notes
    [2] - Reporting group = ITT population (i.e. all randomised participants)
    [3] - Reporting group = ITT population
    Statistical analysis title
    		 Statistical Analysis of PFS
    Statistical analysis description
    Total 128 events (progression/death) provided 80% power to detect a hazard ratio (HR) of 1.45 (erlotinib versus dacomitinib arm) with 1-sided alpha=0.10. This represented a 45% improvement in true median PFS. HR and 95% confidence interval estimated from stratified Cox regression; 2-sided p-value was based on stratified log-rank test with EGFR status, KRAS status, and baseline Eastern Cooperative Oncology Group (ECOG) as stratification factors.
    Comparison groups
    Erlotinib v Dacomitinib
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.012 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.657
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.472
         upper limit
    		 0.914
    Notes
    [4] - 2-Sided Point estimate of HR and its 95% CI were Dacomitinib vs Erlotinib

    Secondary: Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

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    End point title
    		 Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30: included global health status/quality of life (QoL), functional (Fn) scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnoea, appetite loss, insomnia, constipation, diarrhoea, and financial difficulties). Scores were averaged, transformed to 0-100 scale; higher score for Global Qol/Fn scales=better level of QoL/functioning or higher score for symptom scales/items=greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline: for Global QoL/Fn scales >=10; for symptom scale/item <=-10), Worsened (if average scales change from baseline: for Global QoL/Fn scales <=-10; for symptom scale/item >=10), and Stable (if average scales change from baseline >-10 but <10 for Global QoL/Fn scales and symptom scale/item) and participants in each category are reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 44 (Week 188)
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    88 [5]
    90 [6]
    Units: Participants
        Global QoL: Improved (n= 85, 85)
    14
    11
        Global QoL: Worsened (n= 85, 85)
    36
    34
        Global QoL: Stable (n= 85, 85)
    35
    40
        Physical Functioning: Improved (n= 86, 88)
    12
    14
        Physical Functioning: Worsened (n= 86, 88)
    25
    24
        Physical Functioning: Stable (n= 86, 88)
    49
    50
        Role Functioning: Improved (n= 86, 88)
    18
    22
        Role Functioning: Worsened (n= 86, 88)
    38
    31
        Role Functioning: Stable (n= 86, 88)
    30
    35
        Cognitive Functioning: Improved (n= 86, 85)
    13
    15
        Cognitive Functioning: Worsened (n= 86, 85)
    21
    21
        Cognitive Functioning: Stable (n= 86, 85)
    52
    49
        Emotional Functioning: Improved (n= 86, 85)
    11
    21
        Emotional Functioning: Worsened (n= 86, 85)
    27
    26
        Emotional Functioning: Stable (n= 86, 85)
    48
    38
        Social Functioning: Improved (n= 86, 85)
    24
    30
        Social Functioning: Worsened (n= 86, 85)
    30
    19
        Social Functioning: Stable (n= 86, 85)
    32
    36
        Fatigue: Improved (n= 86, 87)
    18
    21
        Fatigue: Worsened (n= 86, 87)
    38
    35
        Fatigue: Stable (n= 86, 87)
    30
    31
        Pain: Improved (n= 86, 87)
    19
    19
        Pain: Worsened (n= 86, 87)
    30
    34
        Pain: Stable (n= 86, 87)
    37
    34
        Nausea and Vomiting: Improved (n= 86, 87)
    13
    13
        Nausea and Vomiting: Worsened (n= 86, 87)
    27
    26
        Nausea and Vomiting: Stable (n= 86, 87)
    46
    48
        Dyspnea: Improved (n= 86, 88)
    23
    25
        Dyspnea: Worsened (n= 86, 88)
    26
    25
        Dyspnea: Stable (n= 86, 88)
    37
    38
        Loss of Appetite: Improved (n= 85, 87)
    17
    19
        Loss of Appetite: Worsened (n= 85, 87)
    41
    43
        Loss of Appetite: Stable (n= 85, 87)
    27
    25
        Insomnia: Improved (n= 86, 87)
    23
    22
        Insomnia: Worsened (n= 86, 87)
    32
    33
        Insomnia: Stable (n= 86, 87)
    31
    32
        Constipation: Improved (n= 86, 85)
    25
    32
        Constipation: Worsened (n= 86, 85)
    16
    13
        Constipation: Stable (n= 86, 85)
    45
    40
        Diarrhea: Improved (n= 86, 85)
    6
    4
        Diarrhea: Worsened (n= 86, 85)
    52
    67
        Diarrhea: Stable (n= 86, 85)
    28
    14
        Financial Difficulties: Improved (n= 85, 86)
    18
    17
        Financial Difficulties: Worsened (n= 85, 86)
    21
    17
        Financial Difficulties: Stable (n= 85, 86)
    46
    51
    Notes
    [5] - Reporting group = ITT population
    [6] - Reporting group = ITT population
    No statistical analyses for this end point

    Secondary: Categorical Summary of Overall Scale Change in EORTC QLQ Lung Cancer Module (LC13)

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    End point title
    		 Categorical Summary of Overall Scale Change in EORTC QLQ Lung Cancer Module (LC13)
    End point description
    QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnoea and 10 single-item symptoms and side effects (coughing, haemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms. Overall scale change was categorized as Improved (if average scales change from baseline <=-10), Worsened (if average scales change from baseline >=10), and Stable (if average scales change from baseline >-10 but <10) and participants in each category are reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 44 (Week 188)
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    88 [7]
    89 [8]
    Units: Participants
        Dyspnoea: Improved (n= 85, 87)
    18
    24
        Dyspnoea: Worsened (n= 85, 87)
    29
    20
        Dyspnoea: Stable (n= 85, 87)
    38
    43
        Coughing: Improved (n= 85, 87)
    24
    37
        Coughing: Worsened (n= 85, 87)
    20
    20
        Coughing: Stable (n= 85, 87)
    41
    30
        Haemoptysis: Improved (n= 85, 86)
    5
    8
        Haemoptysis: Worsened (n= 85, 86)
    10
    10
        Haemoptysis: Stable (n= 85, 86)
    70
    68
        Sore mouth: Improved (n= 85, 87)
    3
    5
        Sore mouth: Worsened (n= 85, 87)
    38
    58
        Sore mouth: Stable (n= 85, 87)
    44
    24
        Dysphagia: Improved (n= 85, 87)
    7
    6
        Dysphagia: Worsened (n= 85, 87)
    24
    35
        Dysphagia: Stable (n= 85, 87)
    54
    46
        Peripheral: Improved (n= 85, 87)
    22
    27
        Peripheral: Worsened (n= 85, 87)
    23
    20
        Peripheral: Stable (n= 85, 87)
    40
    40
        Alopecia: Improved (n= 84, 87)
    20
    21
        Alopecia: Worsened (n= 84, 87)
    13
    21
        Alopecia: Stable (n= 84, 87)
    51
    45
        Pain in chest: Improved (n= 85, 87)
    26
    30
        Pain in chest: Worsened (n= 85, 87)
    21
    13
        Pain in chest: Stable (n= 85, 87)
    38
    44
        Pain in arm or Shoulder: Improved (n= 85, 87)
    19
    28
        Pain in arm or Shoulder: Worsened (n= 85, 87)
    27
    17
        Pain in arm or Shoulder: Stable (n= 85, 87)
    39
    42
        Pain in other parts: Improved (n= 83, 86)
    26
    23
        Pain in other parts: Worsened (n= 83, 86)
    27
    28
        Pain in other parts: Stable (n= 83, 86)
    30
    35
    Notes
    [7] - Reporting group = ITT population
    [8] - Reporting group = ITT population
    No statistical analyses for this end point

    Secondary: Dermatology Life Quality Index (DLQI)

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    End point title
    		 Dermatology Life Quality Index (DLQI)
    End point description
    DLQI: 10-item questionnaire to measure how much the participant’s skin problem has impacted their life over the previous week on following 6 domains: symptoms/feelings (2 questions), daily activities (2 questions), leisure (2 questions), work/school (1 question), personal relationships (2 questions), and treatment (1 question). All questions were answered on a 4-point Likert scale ranging from 0 (not at all/not relevant) to 3 (very much/prevented work or studying). The DLQI total evaluable score was calculated by summing the score of each question and ranged from 0 to 30, where higher scores indicated more quality of life impairment. 9999 = SD could not be determined since n=1 or 0, 999 = arithmetic mean could not be determined since n=1 or 0.
    End point type
    Secondary
    End point timeframe
    Cycle (C) 1 Day (D) 1 (baseline), C1D10-14, D1 of subsequent cycles up to C44
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    87 [9]
    91 [10]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        C1D1 (n= 87, 91)
    0.7 ± 1.97
    0.88 ± 2.38
        C1D10-14 (n=68, 81)
    4.35 ± 6.25
    3.06 ± 4.94
        C2D1 (n= 80, 82)
    5.16 ± 6.29
    3.91 ± 4.07
        C3D1 (n= 63, 63)
    4.08 ± 5.67
    5.52 ± 6.65
        C4D1 (n= 39, 43)
    3.97 ± 4.59
    5.95 ± 6.38
        C5D1 (n= 25, 38)
    3.56 ± 3.61
    5.37 ± 6.08
        C6D1 (n= 16, 27)
    4.13 ± 4.8
    5.37 ± 6.67
        C7D1 (n= 13, 27)
    4.38 ± 4.07
    4.93 ± 6.54
        C8D1 (n= 11, 24)
    4.64 ± 3.14
    5.33 ± 6.23
        C9D1 (n= 11, 19)
    3.82 ± 3.34
    4.84 ± 5.76
        C10D1 (n= 11, 17)
    3.36 ± 3.04
    5.88 ± 7.37
        C11D1 (n= 10, 15)
    5.6 ± 5.13
    6.73 ± 7.57
        C12D1 (n= 7, 14)
    6.71 ± 5.62
    5.5 ± 6.99
        C13D1 (n= 7, 13)
    5.57 ± 4.08
    5.08 ± 7.9
        C14D1 (n= 6, 12)
    6 ± 3.95
    6 ± 7.35
        C15D1 (n= 6, 12)
    4.67 ± 3.78
    5.92 ± 7.4
        C16D1 (n= 5, 11)
    5.4 ± 3.91
    5.36 ± 8.18
        C17D1 (n= 4, 11)
    5 ± 4.24
    5.55 ± 7.85
        C18D1 (n= 4, 10)
    3 ± 2.16
    7.3 ± 9.08
        C19D1 (n= 4, 9)
    4.5 ± 2.38
    7.22 ± 7.73
        C20D1 (n= 2, 10)
    3.5 ± 3.54
    6.5 ± 8.57
        C21D1 (n= 2, 9)
    3.5 ± 2.12
    7.33 ± 7.76
        C22D1 (n= 1, 7)
    1 ± 9999
    2.14 ± 3.67
        C23D1 (n= 1, 7)
    1 ± 9999
    3.71 ± 3.99
        C24D1 (n= 1, 7)
    3 ± 9999
    2.57 ± 4.08
        C25D1 (n= 1, 6)
    8 ± 9999
    2.83 ± 4.45
        C26D1 (n= 0, 6)
    999 ± 9999
    2.67 ± 4.13
        C27D1 (n= 0, 6)
    999 ± 9999
    3.33 ± 3.98
        C28D1 (n= 0, 6)
    999 ± 9999
    3.17 ± 3.82
        C29D1 (n= 0, 6)
    999 ± 9999
    5.33 ± 4.59
        C30D1 (n= 0, 5)
    999 ± 9999
    4.2 ± 5.12
        C31D1 (n= 0, 5)
    999 ± 9999
    4.2 ± 4.97
        C32D1 (n= 0, 4)
    999 ± 9999
    2.75 ± 2.5
        C33D1 (n= 0, 4)
    999 ± 9999
    3 ± 2.94
        C34D1 (n= 0, 2)
    999 ± 9999
    4 ± 1.41
        C35D1 (n= 0, 2)
    999 ± 9999
    12.5 ± 13.44
        C36D1 (n= 0, 2)
    999 ± 9999
    1.5 ± 2.12
        C37D1 (n= 0, 2)
    999 ± 9999
    1.5 ± 2.12
        C38D1 (n= 0, 2)
    999 ± 9999
    0.5 ± 0.71
        C39D1 (n= 0, 2)
    999 ± 9999
    0 ± 0
        C40D1 (n= 0, 2)
    999 ± 9999
    0.5 ± 0.71
        C41D1 (n= 0, 2)
    999 ± 9999
    0 ± 0
        C42D1 (n= 0, 2)
    999 ± 9999
    0.5 ± 0.71
        C43D1 (n= 0, 1)
    999 ± 9999
    3 ± 9999
        C44D1 (n= 0, 0)
    999 ± 9999
    999 ± 999
    Notes
    [9] - Reporting group = ITT population
    [10] - Reporting group = ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Objective Response

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    End point title
    		 Percentage of Participants With Objective Response [11]
    End point description
    Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0. CR: disappearance of all target and non-target lesions. PR: at least 30% decrease in sum of the LDs of target lesions, taking as reference the baseline sum LD. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The baseline period arm for dacomitinib includes only those subjects treated (i.e. the safety population). This outcome measure was analysed for all subjects randomised (i.e. the intention-to-treat [ITT] population).
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    94 [12]
    94 [13]
    Units: percent
        number (confidence interval 95%)
    5.3 (1.7 to 12)
    17 (10 to 26.2)
    Notes
    [12] - Reporting group = ITT population
    [13] - Reporting group = ITT population
    Statistical analysis title
    		 Statistical Analysis of Objective Response
    Comparison groups
    Erlotinib v Dacomitinib
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.011 [14]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - 2-Sided

    Secondary: Best Overall Response (BOR)

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    End point title
    		 Best Overall Response (BOR) [15]
    End point description
    Number of participants with BOR according to RECIST version 1.0: CR= disappearance of all target and non-target lesions. PR= at least 30% decrease in sum of LDs of target lesion, taking as reference baseline sum LD. Stable/no response= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LDs since treatment started. Objective progression= at least a 20% increase in sum of LDs of target lesions, taking as reference the smallest sum of LDs recorded since treatment started and/or unequivocal progression of existing nontarget lesions and/or appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The baseline period arm for dacomitinib includes only those subjects treated (i.e. the safety population). This outcome measure was analysed for all subjects randomised (i.e. the ITT population).
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    94 [16]
    94 [17]
    Units: Participants
        Complete Response
    0
    1
        Partial Response
    5
    15
        Stable/No Response
    37
    32
        Objective Progression
    49
    30
        Indeterminate
    3
    16
    Notes
    [16] - Reporting group = ITT population
    [17] - Reporting group = ITT population
    No statistical analyses for this end point

    Secondary: Duration of Response (DR)

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    End point title
    		 Duration of Response (DR)
    End point description
    Time in weeks from first documentation of objective tumour response to objective tumour progression or symptomatic deterioration or death due to any cause, whichever occurred first. Duration of tumour response was calculated as (the date of the first documentation of objective tumour progression or symptomatic deterioration or death due to any cause or last known progression-free date [if none of the event dates available] minus the date of the first CR or PR [which ever occurred first] that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumour response.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    5 [18]
    16 [19]
    Units: Weeks
        median (confidence interval 95%)
    40.1 (24.7 to 72)
    71.9 (23.6 to 112.1)
    Notes
    [18] - Reporting group = sub-set of ITT population who had a confirmed objective tumour response (CR or PR)
    [19] - Reporting group = sub-set of ITT population who had a confirmed objective tumour response (CR or PR)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS) [20]
    End point description
    Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7.
    End point type
    Secondary
    End point timeframe
    Baseline until end of treatment (15 August 2014); followed up every 8 weeks after discontinuation from study treatment.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The baseline period arm for dacomitinib includes only those subjects treated (i.e. the safety population). This outcome measure was analysed for all subjects randomised (i.e. the ITT population).
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    94 [21]
    94 [22]
    Units: Weeks
        median (confidence interval 95%)
    32.3 (24 to 40.3)
    41.4 (30.4 to 48.1)
    Notes
    [21] - Reporting group = ITT population
    [22] - Reporting group = ITT population
    Statistical analysis title
    		 Statistical Analysis of Overall Survival
    Comparison groups
    Erlotinib v Dacomitinib
    Number of subjects included in analysis
    188
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.252 [24]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.822
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.587
         upper limit
    		 1.151
    Notes
    [23] - HR and its 95% confidence interval were estimated from stratified Cox Regression and 2-sided p-value was based on the stratified log-rank test with EGFR status, KRAS status and baseline ECOG as stratification factors.
    [24] - 2-Sided Point estimate of HR and its 95% CI were Dacomitinib vs Erlotinib

    Other pre-specified: Number of Participants with KRAS and EGFR Status and EGFR T790M Mutation

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    End point title
    		 Number of Participants with KRAS and EGFR Status and EGFR T790M Mutation [25]
    End point description
    Tumour tissue were analysed at a sponsor-designated laboratory to investigate KRAS and EGFR status (wild type or mutated). Participants who did not provide samples for central laboratory analysis confirmation were classified as “unknown”. Additionally blood specimens were analysed at a sponsor-designated laboratory for T790M mutation in EGFR. EGFR T790M mutation is counted under EGFR Status: Mutant category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The baseline period arm for dacomitinib includes only those subjects treated (i.e. the safety population). This outcome measure was analysed for all subjects randomised (i.e. the ITT population).
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    94 [26]
    94 [27]
    Units: Participants
        EGFR Status: Wild Type
    65
    58
        EGFR Status: Mutant
    11
    19
        EGFR T790M Mutation
    0
    2
        EGFR Status: Unknown
    18
    17
        KRAS Status: Wild Type
    64
    57
        KRAS Status: Mutant
    14
    17
        KRAS Status: Unknown
    16
    20
    Notes
    [26] - Reporting group = ITT population
    [27] - Reporting group = ITT population
    No statistical analyses for this end point

    Other pre-specified: Soluble Protein Biomarkers Level

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    End point title
    		 Soluble Protein Biomarkers Level
    End point description
    Blood specimens were analysed at a sponsor-designated laboratory for analysis of shed proteins/receptors related to HER signalling (EGFR, HER-2, Epithelial-cadherin [E-cadherin]). The data collection after C12D1 was not performed, as there were too few participants across both treatment arms after C12D1.
    End point type
    Other pre-specified
    End point timeframe
    C1D1 (baseline), D1 of each subsequent cycle up to end of treatment (up to 121 weeks)
    End point values
    		 Erlotinib Dacomitinib
    Number of subjects analysed
    76 [28]
    73 [29]
    Units: nanogram(s) per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        EGFR, C1D1 (n= 65, 66)
    49.88 ± 7.513
    49.44 ± 9.286
        EGFR, C2D1 (n= 76, 73)
    48.87 ± 6.985
    41.29 ± 8.132
        EGFR, C3D1 (n= 43, 53)
    51.28 ± 6.925
    42.39 ± 8.072
        EGFR, C4D1 (n= 26, 39)
    49.49 ± 8.41
    41.9 ± 8.793
        EGFR, C5D1 (n= 16, 29)
    48.58 ± 5.801
    41.97 ± 7.974
        EGFR, C6D1 (n= 15, 27)
    50.32 ± 7.073
    42.82 ± 8.014
        EGFR, C7D1 (n= 13, 26)
    52.16 ± 7.449
    43.16 ± 9.13
        EGFR, C8D1 (n= 10, 21)
    54.74 ± 10.73
    44.78 ± 9.673
        EGFR, C9D1 (n= 8, 17)
    55.38 ± 12.888
    47.89 ± 10.854
        EGFR, C10D1 (n= 10, 17)
    54.57 ± 9.244
    48.12 ± 13.105
        EGFR, C11D1 (n= 7, 14)
    59.63 ± 14.624
    50.9 ± 13.667
        EGFR, C12D1 (n= 6, 13)
    57.65 ± 11.503
    52.39 ± 12.976
        HER2, C1D1 (n= 65,66)
    10.89 ± 15.44
    8.39 ± 2.05
        HER2, C2D1 (n= 76,73)
    9.17 ± 4.946
    6.42 ± 2.12
        HER2, C3D1 (n= 43,53)
    9.26 ± 6.383
    6.17 ± 1.703
        HER2, C4D1 (n= 26,39)
    9.51 ± 6.958
    6.29 ± 1.716
        HER2, C5D1 (n= 16,29)
    7.7 ± 1.79
    5.96 ± 1.342
        HER2, C6D1 (n= 15,27)
    7.45 ± 2.414
    6.34 ± 1.428
        HER2, C7D1 (n= 13,26)
    8.07 ± 2.262
    6.47 ± 1.773
        HER2, C8D1 (n= 10,21)
    7.28 ± 1.279
    7.15 ± 3.168
        HER2, C9D1 (n= 8,17)
    7.32 ± 1.204
    6.87 ± 2.205
        HER2, C10D1 (n= 10,17)
    7.49 ± 1.618
    7.25 ± 2.883
        HER2, C11D1 (n= 7,14)
    7.76 ± 1.735
    6.56 ± 1.333
        HER2, C12D1 (n= 6,13)
    7.15 ± 1.57
    6.57 ± 1.587
        E-cadherin, C1D1 (n= 65, 66)
    51.71 ± 14.63
    56.13 ± 22.694
        E-cadherin, C2D1 (n= 76. 73)
    41.46 ± 14.982
    45.4 ± 18.149
        E-cadherin, C3D1 (n= 43, 53)
    42.58 ± 13.284
    42.28 ± 17.81
        E-cadherin, C4D1 (n= 26, 39)
    40.51 ± 12.384
    40.15 ± 16.105
        E-cadherin, C5D1 (n= 16, 29)
    37.58 ± 9.951
    38.15 ± 10.913
        E-cadherin, C6D1 (n= 15, 27)
    36.78 ± 7.695
    39.16 ± 10.301
        E-cadherin, C7D1 (n= 13, 26)
    38.33 ± 9.675
    39.47 ± 11.977
        E-cadherin, C8D1 (n= 10, 21)
    43.6 ± 11.661
    40.94 ± 13.698
        E-cadherin, C9D1 (n= 8,17)
    40.26 ± 8.146
    38.97 ± 12.517
        E-cadherin, C10D1 (n= 10, 17)
    40.29 ± 15.742
    45.85 ± 12.244
        E-cadherin, C11D1 (n= 7, 14)
    35.9 ± 9.239
    39.44 ± 8.968
        E-cadherin, C12D1 (n= 6, 13)
    35.48 ± 8.637
    40.3 ± 12.433
    Notes
    [28] - Reporting group = biomarker analysis population
    [29] - Reporting group = biomarker analysis population
    No statistical analyses for this end point

    Other pre-specified: Trough Plasma Concentration (Ctrough) of Dacomitinib (PF-00299804)

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    End point title
    		 Trough Plasma Concentration (Ctrough) of Dacomitinib (PF-00299804) [30]
    End point description
    Only participants from “Dacomitinib” treatment arm were planned to be analysed for this outcome.
    End point type
    Other pre-specified
    End point timeframe
    C1D10-14, C2D1, C3D1, C4D1
    Notes
    [30] - 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: Only participants from “Dacomitinib” treatment arm were planned to be analysed for this end point.
    End point values
    		 Dacomitinib
    Number of subjects analysed
    63 [31]
    Units: ng /mL
    arithmetic mean (standard deviation)
        C1D10-14 (n= 63)
    71.94 ± 37.496
        C2D1 (n= 60)
    65.5 ± 33.292
        C3D1 (n= 44)
    59.28 ± 30.089
        C4D1 (n= 31)
    57.79 ± 26.206
    Notes
    [31] - Reporting group = Pharmacokinetic population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from the time that the participant provided informed consent through and including 28 calendar days after the last administration of the investigational product.
    Adverse event reporting additional description
    The same event may appear as both an AE and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or 1 participant may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    		 Erlotinib 150 milligram (mg) tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumor progression or death.

    Reporting group title
    Dacomitinib
    Reporting group description
    		 Dacomitinib (PF-00299804) 45 mg tablet orally once daily continuously in 28-day cycles until unacceptable toxicity, tumor progression or death.

    Serious adverse events
    		 Erlotinib Dacomitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 94 (31.91%)
    34 / 93 (36.56%)
         number of deaths (all causes)
    17
    17
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         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
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    12 / 94 (12.77%)
    9 / 93 (9.68%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 9
         deaths causally related to treatment / all
    0 / 12
    0 / 9
    Fatigue
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 94 (3.19%)
    8 / 93 (8.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 94 (3.19%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (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
    Altered state of consciousness
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (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
    2 / 94 (2.13%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 94 (2.13%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 94 (1.06%)
    2 / 93 (2.15%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (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
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         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
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 94 (4.26%)
    6 / 93 (6.45%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 8
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Pneumonia bacterial
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 93 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Erlotinib Dacomitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 94 (98.94%)
    93 / 93 (100.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 94 (13.83%)
    18 / 93 (19.35%)
         occurrences all number
    16
    25
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 94 (9.57%)
    3 / 93 (3.23%)
         occurrences all number
    9
    4
    Dysgeusia
         subjects affected / exposed
    7 / 94 (7.45%)
    7 / 93 (7.53%)
         occurrences all number
    7
    9
    Headache
         subjects affected / exposed
    8 / 94 (8.51%)
    3 / 93 (3.23%)
         occurrences all number
    9
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 93 (6.45%)
         occurrences all number
    6
    9
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 94 (11.70%)
    13 / 93 (13.98%)
         occurrences all number
    13
    18
    Chest pain
         subjects affected / exposed
    13 / 94 (13.83%)
    5 / 93 (5.38%)
         occurrences all number
    15
    6
    Fatigue
         subjects affected / exposed
    33 / 94 (35.11%)
    24 / 93 (25.81%)
         occurrences all number
    41
    30
    Mucosal inflammation
         subjects affected / exposed
    7 / 94 (7.45%)
    23 / 93 (24.73%)
         occurrences all number
    7
    34
    Oedema peripheral
         subjects affected / exposed
    4 / 94 (4.26%)
    6 / 93 (6.45%)
         occurrences all number
    5
    7
    Pain
         subjects affected / exposed
    6 / 94 (6.38%)
    5 / 93 (5.38%)
         occurrences all number
    6
    6
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 94 (3.19%)
    6 / 93 (6.45%)
         occurrences all number
    3
    11
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    7 / 94 (7.45%)
    2 / 93 (2.15%)
         occurrences all number
    8
    4
    Cheilitis
         subjects affected / exposed
    1 / 94 (1.06%)
    5 / 93 (5.38%)
         occurrences all number
    1
    18
    Constipation
         subjects affected / exposed
    12 / 94 (12.77%)
    9 / 93 (9.68%)
         occurrences all number
    12
    10
    Diarrhoea
         subjects affected / exposed
    46 / 94 (48.94%)
    67 / 93 (72.04%)
         occurrences all number
    59
    145
    Dry mouth
         subjects affected / exposed
    8 / 94 (8.51%)
    9 / 93 (9.68%)
         occurrences all number
    8
    11
    Dyspepsia
         subjects affected / exposed
    8 / 94 (8.51%)
    3 / 93 (3.23%)
         occurrences all number
    9
    4
    Mouth ulceration
         subjects affected / exposed
    5 / 94 (5.32%)
    3 / 93 (3.23%)
         occurrences all number
    5
    3
    Nausea
         subjects affected / exposed
    21 / 94 (22.34%)
    20 / 93 (21.51%)
         occurrences all number
    24
    23
    Stomatitis
         subjects affected / exposed
    10 / 94 (10.64%)
    27 / 93 (29.03%)
         occurrences all number
    14
    38
    Vomiting
         subjects affected / exposed
    14 / 94 (14.89%)
    11 / 93 (11.83%)
         occurrences all number
    16
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 94 (22.34%)
    17 / 93 (18.28%)
         occurrences all number
    24
    24
    Dysphonia
         subjects affected / exposed
    0 / 94 (0.00%)
    6 / 93 (6.45%)
         occurrences all number
    0
    8
    Dyspnoea
         subjects affected / exposed
    16 / 94 (17.02%)
    20 / 93 (21.51%)
         occurrences all number
    17
    24
    Epistaxis
         subjects affected / exposed
    2 / 94 (2.13%)
    7 / 93 (7.53%)
         occurrences all number
    3
    9
    Haemoptysis
         subjects affected / exposed
    3 / 94 (3.19%)
    9 / 93 (9.68%)
         occurrences all number
    3
    11
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    11 / 94 (11.70%)
    12 / 93 (12.90%)
         occurrences all number
    17
    20
    Alopecia
         subjects affected / exposed
    3 / 94 (3.19%)
    9 / 93 (9.68%)
         occurrences all number
    4
    12
    Dermatitis acneiform
         subjects affected / exposed
    54 / 94 (57.45%)
    60 / 93 (64.52%)
         occurrences all number
    77
    124
    Dry skin
         subjects affected / exposed
    15 / 94 (15.96%)
    22 / 93 (23.66%)
         occurrences all number
    21
    47
    Erythema multiforme
         subjects affected / exposed
    4 / 94 (4.26%)
    10 / 93 (10.75%)
         occurrences all number
    5
    12
    Exfoliative rash
         subjects affected / exposed
    14 / 94 (14.89%)
    16 / 93 (17.20%)
         occurrences all number
    24
    37
    Nail disorder
         subjects affected / exposed
    1 / 94 (1.06%)
    7 / 93 (7.53%)
         occurrences all number
    2
    13
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    5 / 94 (5.32%)
    11 / 93 (11.83%)
         occurrences all number
    6
    14
    Pruritus
         subjects affected / exposed
    15 / 94 (15.96%)
    14 / 93 (15.05%)
         occurrences all number
    18
    27
    Skin fissures
         subjects affected / exposed
    2 / 94 (2.13%)
    9 / 93 (9.68%)
         occurrences all number
    3
    20
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 94 (5.32%)
    2 / 93 (2.15%)
         occurrences all number
    5
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 94 (10.64%)
    11 / 93 (11.83%)
         occurrences all number
    10
    12
    Pain in extremity
         subjects affected / exposed
    2 / 94 (2.13%)
    5 / 93 (5.38%)
         occurrences all number
    2
    5
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 94 (3.19%)
    9 / 93 (9.68%)
         occurrences all number
    4
    10
    Paronychia
         subjects affected / exposed
    8 / 94 (8.51%)
    24 / 93 (25.81%)
         occurrences all number
    11
    58
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 94 (6.38%)
    3 / 93 (3.23%)
         occurrences all number
    6
    5
    Urinary tract infection
         subjects affected / exposed
    6 / 94 (6.38%)
    5 / 93 (5.38%)
         occurrences all number
    6
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    29 / 94 (30.85%)
    27 / 93 (29.03%)
         occurrences all number
    36
    31

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2013
    Protocol Amendment 2 updated dosing language, allowed less frequent tumor assessment imaging for participants on therapy over 1 year (with Sponsor approval), provided information on the single reference safety documents used in the study, revised pregnancy/contraception language, updated dacomitinib concomitant medication guide for those drugs dependent on cytochrome P450 2D6 for metabolism and use of acid reducing agents, based on recent clinical pharmacology analyses, revised reporting of dose errors as AEs, included 3 additional strengths for dacomitinib film coated tablets (15, 30, and 45 mg), included clarifying language on active reporting period and necessity to report SAEs post-active reporting period to align with CT-3 and Food and Drug Administration Final Rule, updated instructions for evaluation of liver function changes and updated wording and format to align with changes in the Pfizer protocol template.

    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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