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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase III Study of First-Line Maintenance Tarceva® Versus Tarceva at the Time of Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Not Progressed Following 4 Cycles of Platinum-Based Chemotherapy

    Summary
    EudraCT number
    		 2010-024468-16
    Trial protocol
    		 SK   HU   CZ   LV   LT   NL   FR   BG   IT  
    Global end of trial date
    22 Jan 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    22 Sep 2016
    First version publication date
    01 May 2016
    Other versions
    		 v1 , v2
    Version creation reason
    • New data added to full data set
    Update data

    Trial information

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    Trial identification
    Sponsor protocol code
    BO25460
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01328951
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    26 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study evaluated the benefit of first-line maintenance erlotinib versus erlotinib at the time of disease progression in participants with advanced non-small cell lung cancer (NSCLC) who have not progressed following 4 cycles of platinum-based chemotherapy and whose tumor does not harbor an epidermal growth factor receptor (EGFR) activating mutation. The study included three periods: a Blinded Period (BP), an Open-Label Period (OLP) and a final Survival Follow-Up (SFU) period.
    Protection of trial subjects
    The study was conducted in full conformance with the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded greater protection to the participant. The study has fully adhered to the principles outlined in the Guideline for Good Clinical Practice (GCP) International Conference on Harmonisation (ICH) Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. For study sites in the European Union (EU)/European Economic Area (EEA), the study has also complied with the EU Clinical Trial Directive (2001/20/EC). For study sites in the United States (US) or under the US Investigational New Drug application (IND), the study has also adhered to the basic principles of GCP as outlined in the current version of 21 Code of Federal Regulations (CFR), subchapter D, part 312, “Responsibilities of Sponsors and Investigators”; part 50, “Protection of Human Subjects”; and part 56, “Institutional Review Boards”. In other countries where Guidelines for GCP exist, the Sponsor and the investigators have strictly ensured adherence to the stated provision.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jul 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 51 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 61
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Romania: 53
    Country: Number of subjects enrolled
    Thailand: 54
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Ukraine: 87
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    South Africa: 30
    Country: Number of subjects enrolled
    Brazil: 37
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Bulgaria: 80
    Country: Number of subjects enrolled
    Czech Republic: 32
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Hungary: 44
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    Latvia: 7
    Country: Number of subjects enrolled
    Lithuania: 28
    Worldwide total number of subjects
    643
    EEA total number of subjects
    341
    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)
    420
    From 65 to 84 years
    220
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of three periods: a BP, an OLP, and final SFU. These periods were not necessarily sequential, because the OLP could be "skipped" in select participants. Therefore, the reasons for discontinuation are presented altogether within the Overall Study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Participants received double-blinded treatment during the BP; however, open-label treatment was administered during the OLP.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Late Erlotinib
    Arm description
    		 Participants received blinded placebo tablets orally (PO) once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive second-line erlotinib tablets during the OLP as 150 milligrams (mg) PO once daily, provided by the Sponsor. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as film-coated tablets PO once daily during the BP until disease progression, death, or unacceptable toxicity.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered during either the BP (for Early Erlotinib) or the OLP (for Late Erlotinib) as 150 mg PO once daily until disease progression, death, or unacceptable toxicity.

    Arm title
    		 Early Erlotinib
    Arm description
    		 Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive an approved second-line therapy (but not EGFR targeted therapies) or best supportive care (BSC) as chosen by the investigator during the OLP. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib was administered during either the BP (for Early Erlotinib) or the OLP (for Late Erlotinib) as 150 mg PO once daily until disease progression, death, or unacceptable toxicity.

    Number of subjects in period 1
    		Late Erlotinib Early Erlotinib
    Started
    321
    322
    Completed
    0
    0
    Not completed
    321
    322
         Disease progression
    17
    14
         Death
    243
    258
         Not specified
    11
    6
         Adverse event
    2
    -
         Lost to follow-up
    6
    7
         Withdrawal by subject
    6
    6
         Study closed by the Sponsor
    36
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Late Erlotinib
    Reporting group description
    		 Participants received blinded placebo tablets orally (PO) once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive second-line erlotinib tablets during the OLP as 150 milligrams (mg) PO once daily, provided by the Sponsor. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.

    Reporting group title
    Early Erlotinib
    Reporting group description
    		 Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive an approved second-line therapy (but not EGFR targeted therapies) or best supportive care (BSC) as chosen by the investigator during the OLP. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.

    Reporting group values
    		 Late Erlotinib Early Erlotinib Total
    Number of subjects
    		 321 322 643
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.6 ( 9.1 ) 60.8 ( 8.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 77 84 161
        Male
    		 244 238 482

    End points

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    End points reporting groups
    Reporting group title
    Late Erlotinib
    Reporting group description
    		 Participants received blinded placebo tablets orally (PO) once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive second-line erlotinib tablets during the OLP as 150 milligrams (mg) PO once daily, provided by the Sponsor. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.

    Reporting group title
    Early Erlotinib
    Reporting group description
    		 Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive an approved second-line therapy (but not EGFR targeted therapies) or best supportive care (BSC) as chosen by the investigator during the OLP. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol.

    Subject analysis set title
    Placebo (Late Erlotinib)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received blinded placebo tablets PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity.

    Subject analysis set title
    Erlotinib (Early Erlotinib)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity.

    Primary: Percentage of Participants Who Died During the Overall Study

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    End point title
    		 Percentage of Participants Who Died During the Overall Study [1]
    End point description
    Participants were followed for survival until death or premature withdrawal. The percentage of participants who died during the Overall Study (BP, OLP, or SFU) was calculated. Intent-to-Treat (ITT) Population: All participants who were randomized to treatment.
    End point type
    Primary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP; per local standards during OLP; then every 12 weeks during SFU until death)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint reflects the percentage of participants with the event of interest. Statistical analysis was performed on the time-to-event endpoint.
    End point values
    		 Late Erlotinib Early Erlotinib
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (not applicable)
    73.2
    75.2
    No statistical analyses for this end point

    Primary: Overall Survival (OS) as Median Time to Event During the Overall Study

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    End point title
    		 Overall Survival (OS) as Median Time to Event During the Overall Study
    End point description
    Participants were followed for survival until death or premature withdrawal. OS was defined as the interval between date of randomization and date of death from any cause. Median time to event during the Overall Study (BP, OLP, or SFU) was estimated using the Kaplan-Meier method and expressed in months. ITT Population.
    End point type
    Primary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP; per local standards during OLP; then every 12 weeks during SFU until death)
    End point values
    		 Late Erlotinib Early Erlotinib
    Number of subjects analysed
    321
    322
    Units: months
        median (confidence interval 95%)
    9.46 (8.38 to 11.33)
    9.72 (8.57 to 11.17)
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Late Erlotinib v Early Erlotinib
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.8183
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.85
         upper limit
    		 1.22
    Notes
    [2] - The HR and 95% confidence interval (CI) were estimated by Cox regression.
    Statistical analysis title
    		 Stratified Analysis
    Statistical analysis description
    Stratified according to tumor histology, stage of disease, objective response at Baseline, bevacizumab use, smoking status, and region of enrollment.
    Comparison groups
    Late Erlotinib v Early Erlotinib
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.5256
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.32
    Notes
    [3] - The HR and 95% CI were estimated by Cox regression.

    Primary: Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study

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    End point title
    		 Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study
    End point description
    Participants were followed for survival until death or premature withdrawal. The percentage of participants event-free (i.e., still alive) at 1 year during the Overall Study was calculated. ITT Population.
    End point type
    Primary
    End point timeframe
    At 1 year
    End point values
    		 Late Erlotinib Early Erlotinib
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (confidence interval 95%)
    41.75 (36.2 to 47.3)
    42.15 (36.6 to 47.7)
    Statistical analysis title
    		 Difference in Event-Free Rate
    Comparison groups
    Late Erlotinib v Early Erlotinib
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9207
    Method
    		 Chi-squared
    Parameter type
    		 Difference in event-free rate
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.25
         upper limit
    		 7.45

    Secondary: Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment

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    End point title
    		 Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment
    End point description
    Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and ≥5-millimiter (mm) increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants who died or experienced disease progression during the BP was calculated. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (not applicable)
    95
    94.1
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment

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    End point title
    		 Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment
    End point description
    Tumor response was evaluated using RECIST version 1.1. Disease progression was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. PFS was defined as the interval between date of randomization and date of first documented death or disease progression. Median time to event during the BP was estimated using the Kaplan-Meier method and expressed in weeks. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: weeks
        median (full range (min-max))
    12 (11.71 to 12.29)
    13 (12.14 to 17.43)
    Statistical analysis title
    		 Unstratified Analysis
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.4759
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.11
    Notes
    [4] - The HR and 95% CI were estimated by Cox regression.
    Statistical analysis title
    		 Stratified Analysis
    Statistical analysis description
    Stratified according to tumor histology, stage of disease, objective response at Baseline, bevacizumab use, smoking status, and region of enrollment.
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.1635
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.06
    Notes
    [5] - The HR and 95% CI were estimated by Cox regression.

    Secondary: Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment

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    End point title
    		 Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment
    End point description
    Tumor response was evaluated using RECIST version 1.1. Disease progression was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants event-free (i.e., still alive and without disease progression) at 6 months during the BP was calculated. ITT Population.
    End point type
    Secondary
    End point timeframe
    At 6 months
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (confidence interval 95%)
    24.22 (19.5 to 28.94)
    27.11 (22.19 to 32.02)
    Statistical analysis title
    		 Difference in Event-Free Rate
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4069
    Method
    		 Chi-squared
    Parameter type
    		 Difference in event-free rate
    Point estimate
    -2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.7
         upper limit
    		 3.93

    Secondary: Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment

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    End point title
    		 Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment
    End point description
    Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. The percentage of participants with a best overall response of either CR or PR (i.e., the objective response rate [ORR]) during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (confidence interval 95%)
    3.7 (1.95 to 6.44)
    6.5 (4.08 to 9.8)
    Statistical analysis title
    		 Difference in Response Rate
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.1097
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rate
    Point estimate
    2.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 6.35
    Notes
    [6] - The 95% CI for difference in response rates was constructed using the Anderson-Hauck method.
    Statistical analysis title
    		 Odds Ratio
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 3.72
    Notes
    [7] - The 95% CI for OR was constructed using the Wald method.

    Secondary: Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment

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    End point title
    		 Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment
    End point description
    Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. Stable disease (SD) was defined as neither sufficient shrinkage in target lesions to qualify for PR nor sufficient growth to qualify for disease progression. Disease progression (progressive disease/PD) was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants with each level of best tumor response during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: percentage of participants
    number (confidence interval 95%)
        CR
    0.6 (0.08 to 2.23)
    0.9 (0.19 to 2.7)
        PR
    3.1 (1.5 to 5.65)
    5.6 (3.35 to 8.69)
        SD
    55.5 (49.83 to 60.97)
    54.7 (49.04 to 60.19)
        PD
    38.6 (33.27 to 44.2)
    32.3 (27.22 to 37.71)
        Missing
    2.2 (0.88 to 4.44)
    6.5 (4.08 to 9.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment

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    End point title
    		 Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment
    End point description
    Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. SD was defined as neither sufficient shrinkage in target lesions to qualify for PR nor sufficient growth to qualify for disease progression. The percentage of participants with a best overall response of CR, PR, or SD (i.e., the disease control rate [DCR]) during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
    End point values
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib)
    Number of subjects analysed
    321
    322
    Units: percentage of participants
        number (confidence interval 95%)
    59.2 (53.59 to 64.62)
    61.2 (55.62 to 66.53)
    Statistical analysis title
    		 Difference in Response Rate
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.6062
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rate
    Point estimate
    1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.74
         upper limit
    		 9.72
    Notes
    [8] - The 95% CI for difference in response rates was constructed using the Anderson-Hauck method.
    Statistical analysis title
    		 Odds Ratio
    Comparison groups
    Placebo (Late Erlotinib) v Erlotinib (Early Erlotinib)
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.49
    Notes
    [9] - The 95% CI for OR was constructed using the Wald method.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 4.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until disease progression, death, or unacceptable toxicity during BP; per local standards and 28 days after last visit during OLP)
    Adverse event reporting additional description
    Safety Population: All participants who received at least one dose of study treatment, according to drug actually received. Non-serious adverse events (NSAEs) were not collected in the OLP. Hence, 0 participants would be affected under "Non-Serious Adverse Events". However, an NSAE in 1 participant was reported to Roche outside protocol.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo (Late Erlotinib)
    Reporting group description
    		 Participants received blinded placebo tablets PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity.

    Reporting group title
    Erlotinib (Early Erlotinib)
    Reporting group description
    		 Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity.

    Reporting group title
    Second-Line Erlotinib (Late Erlotinib)
    Reporting group description
    		 Participants who received blinded placebo and who demonstrated disease progression were unblinded and could receive second-line erlotinib as 150-mg tablets PO once daily, provided by the Sponsor. This treatment continued during the OLP until disease progression, death, or unacceptable toxicity.

    Reporting group title
    Second-Line Chemotherapy (Early Erlotinib)
    Reporting group description
    		 Participants who received blinded erlotinib and who demonstrated disease progression were unblinded and could receive an approved second-line therapy (but not EGFR targeted therapies) or BSC as chosen by the investigator. This treatment continued during the OLP until disease progression, death, or unacceptable toxicity.

    Serious adverse events
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib) Second-Line Erlotinib (Late Erlotinib) Second-Line Chemotherapy (Early Erlotinib)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 319 (8.46%)
    36 / 322 (11.18%)
    23 / 248 (9.27%)
    8 / 162 (4.94%)
         number of deaths (all causes)
    11
    25
    51
    31
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Meningeal neoplasm
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Finger amputation
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 319 (0.63%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perforated ulcer
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 319 (0.94%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    3 / 248 (1.21%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 322 (0.62%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 322 (0.62%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 319 (0.00%)
    4 / 322 (1.24%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 322 (0.62%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 322 (0.62%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 319 (0.31%)
    2 / 322 (0.62%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    2 / 248 (0.81%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorroids thrombosed
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 319 (0.00%)
    2 / 322 (0.62%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin mass
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impetigo
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 319 (0.94%)
    4 / 322 (1.24%)
    2 / 248 (0.81%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 6
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 319 (0.31%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 319 (0.00%)
    0 / 322 (0.00%)
    0 / 248 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 319 (0.00%)
    1 / 322 (0.31%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo (Late Erlotinib) Erlotinib (Early Erlotinib) Second-Line Erlotinib (Late Erlotinib) Second-Line Chemotherapy (Early Erlotinib)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 319 (33.54%)
    206 / 322 (63.98%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    11 / 319 (3.45%)
    17 / 322 (5.28%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    12
    20
    0
    0
    Fatigue
         subjects affected / exposed
    20 / 319 (6.27%)
    21 / 322 (6.52%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    21
    21
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 319 (4.39%)
    78 / 322 (24.22%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    20
    102
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    37 / 319 (11.60%)
    31 / 322 (9.63%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    40
    33
    0
    0
    Dyspnoea
         subjects affected / exposed
    23 / 319 (7.21%)
    27 / 322 (8.39%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    25
    28
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 319 (0.94%)
    17 / 322 (5.28%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    3
    20
    0
    0
    Rash
    Additional description: Per protocol, NSAEs were not collected in the OLP. However, an NSAE in 1 participant in the "Second-Line Erlotinib (Late Erlotinib)" arm was reported outside protocol and coded with MedDRA (18.1). As such, this single event is presented in the table.
         subjects affected / exposed
    32 / 319 (10.03%)
    127 / 322 (39.44%)
    1 / 248 (0.40%)
    0 / 162 (0.00%)
         occurrences all number
    33
    148
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 319 (0.94%)
    17 / 322 (5.28%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    4
    21
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    11 / 319 (3.45%)
    21 / 322 (6.52%)
    0 / 248 (0.00%)
    0 / 162 (0.00%)
         occurrences all number
    11
    24
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Feb 2013
    The protocol was amended primarily to allow a lower dose of carboplatin in combination with pemetrexed during the screening phase. Additional minor updates/clarifications were provided for several aspects of the protocol including adverse event reporting, dose modification, administration and unblinding, data collection, and recruitment.

    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.
    Following the final analysis, the study was closed and all remaining participants were withdrawn from the study and considered "Not Completed" (as presented under Subject Disposition). However, the overall status of study was confirmed as completed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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