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    Clinical Trial Results:
    A Randomized, Phase III, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMAb) in Combination with Tarceva® (Erlotinib) in Patients with MET Diagnostic-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Standard Chemotherapy for Advanced or Metastatic Disease.

    Summary
    EudraCT number
    		 2011-002224-40
    Trial protocol
    		 BE   ES   DE   HU   IE   NL   GB   IT   PL  
    Global end of trial date
    28 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2016
    First version publication date
    07 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OAM4971g
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01456325
    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 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann La Roche AG, +41 61 6878333, 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
    14 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine whether the combination of onartuzumab + erlotinib was superior (in terms of overall survival [OS]) to placebo + erlotinib after standard platinum-based chemotherapy in participants with MET diagnostic-positive NSCLC.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Netherlands: 14
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Japan: 56
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 57
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    South Africa: 4
    Country: Number of subjects enrolled
    United States: 164
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Chile: 4
    Worldwide total number of subjects
    499
    EEA total number of subjects
    196
    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)
    295
    From 65 to 84 years
    204
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Second and third-line NSCLC participants with at least 1 prior platinum based line of therapy, were tested for MET status and endothelial growth factor receptor (EGFR) mutation status, and MET diagnostic positive participants were randomized in 1:1 ratio to either "onartuzumab+erlotinib" or "placebo+erlotinib".

    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, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Onartuzumab+Erlotinib
    Arm description
    		 Participants received onartuzumab 15 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally once daily (QD) from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Onartuzumab
    Investigational medicinal product code
    RO5490258
    Other name
    MetMab
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received onartuzumab 15 mg/kg IV infusion on Day 1 of every 3-week cycle.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received erlotinib 150 mg tablet orally once daily from Day 1, Cycle 1.

    Arm title
    		 Placebo+Erlotinib
    Arm description
    		 Participants received onartuzumab matching placebo on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally QD from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravascular use
    Dosage and administration details
    Participants received onartuzumab matching placebo on Day 1 of every 3-week cycle.

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received erlotinib 150 mg tablet orally once daily from Day 1, Cycle 1.

    Number of subjects in period 1
    		Onartuzumab+Erlotinib Placebo+Erlotinib
    Started
    250
    249
    Completed
    0
    0
    Not completed
    250
    249
         Disease progression
    2
    -
         Consent withdrawn by subject
    13
    10
         Disease progression
    -
    5
         Death
    185
    180
         Unspecified
    1
    2
         Lost to follow-up
    4
    1
         Sponsor decision
    44
    50
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Onartuzumab+Erlotinib
    Reporting group description
    		 Participants received onartuzumab 15 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally once daily (QD) from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Reporting group title
    Placebo+Erlotinib
    Reporting group description
    		 Participants received onartuzumab matching placebo on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally QD from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Reporting group values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib Total
    Number of subjects
    		 250 249 499
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.4 ± 10 61.5 ± 10.2 -
    Gender categorical
    Units: Subjects
        Female
    		 111 110 221
        Male
    		 139 139 278

    End points

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    End points reporting groups
    Reporting group title
    Onartuzumab+Erlotinib
    Reporting group description
    		 Participants received onartuzumab 15 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally once daily (QD) from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Reporting group title
    Placebo+Erlotinib
    Reporting group description
    		 Participants received onartuzumab matching placebo on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg tablet orally QD from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from date of randomization until death from any cause. OS was estimated using Kaplan-Meier method and 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT population was considered for analysis of this end point.
    End point type
    Primary
    End point timeframe
    Randomization until death (up to approximately 18 months) (assessed at the treating physician's discretion using the local standard-of-care practice)
    End point values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib
    Number of subjects analysed
    250
    249
    Units: months
        median (confidence interval 95%)
    6.8 (6.1 to 7.5)
    9.1 (7.7 to 10.2)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    Strata were: MET immunohistochemistry (IHC) clinical score (2+ versus [vs] 3+), prior lines of therapy (1 vs. 2), histology (non-squamous vs. squamous), and endothelial growth factor receptor (EGFR)-activating mutation status (yes vs. no). Hazard ratios were estimated by Cox regression.
    Comparison groups
    Placebo+Erlotinib v Onartuzumab+Erlotinib
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0677
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.65

    Secondary: Percentage of Participants With Disease Progression or Death

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    End point title
    		 Percentage of Participants With Disease Progression or Death
    End point description
    Progressive disease (PD) was determined based on investigator's assessment using Response Evaluation Criteria in Solid Tumors (RECIST) Version (V) 1.1. PD: At least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of one or more new lesions is also considered progression. ITT population was considered for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Randomization until disease progression or death, whichever occurred first (up to approximately 18 months) (assessed at the treating physician's discretion using the local standard-of-care practice)
    End point values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib
    Number of subjects analysed
    250
    249
    Units: percentage of participants
        number (not applicable)
    84
    81.9
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time between the date of randomization and the date of the first documented disease progression or death, whichever occurred first. Progressive disease (PD): At least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Kaplan-Meier estimates were used for analysis. ITT population was considered for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Randomization until disease progression or death, whichever occurred first (up to approximately 18 months) (assessed at the treating physician's discretion using the local standard-of-care practice)
    End point values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib
    Number of subjects analysed
    250
    249
    Units: months
        median (confidence interval 95%)
    2.7 (2.4 to 2.9)
    2.6 (1.5 to 2.8)
    Statistical analysis title
    		 Stratified analysis
    Statistical analysis description
    Strata were: Met IHC clinical score (2+ vs. 3+), prior lines of therapy (1 vs. 2), histology (nonsquamous vs. squamous), and EGFR activating mutation status (yes vs. no). Hazard ratios were estimated by Cox regression.
    Comparison groups
    Onartuzumab+Erlotinib v Placebo+Erlotinib
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9249
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.2

    Secondary: Percentage of Participants with an Objective Response Assessed Using RECIST V 1.1

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    End point title
    		 Percentage of Participants with an Objective Response Assessed Using RECIST V 1.1
    End point description
    Objective response is defined as a complete response (CR) or partial response (PR). Participants without a post-baseline tumor assessment are considered as non-responders. CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ITT population was considered for analysis of this end point.
    End point type
    Secondary
    End point timeframe
    Randomization until disease progression or death, whichever occurred first (up to approximately 18 months) (assessed at the treating physician's discretion using the local standard-of-care practice)
    End point values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib
    Number of subjects analysed
    250
    249
    Units: percentage of participants
        number (confidence interval 95%)
    8.4 (5.27 to 12.55)
    9.6 (6.27 to 14)
    Statistical analysis title
    		 Statistical analysis I
    Comparison groups
    Onartuzumab+Erlotinib v Placebo+Erlotinib
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6295
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rates
    Point estimate
    -1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.26
         upper limit
    		 3.79

    Secondary: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) Scores

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    End point title
    		 European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) Scores
    End point description
    EORTC QLQ-LC13: consisted of 13 questions with one symptom scale for dyspnea of 3 items and 10 single items (cough, haemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, pain in chest, pain in arm/shoulder, other pain, pain medication). Questions used 4-point scale (1 'Not at all' to 4 'Very much'. Scores were averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. Number of subjects analyzed = number of participants evaluable for this end point and "n" represents number of participants evaluable at the specified time point for the specified symptom scale. When n=0, the mean±standard deviation was reported as 99999±99999; when n=1, the upper confidence interval was reported as "99999" as it is not estimable.
    End point type
    Secondary
    End point timeframe
    Screening, Day 1 of Cycles 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 (cycle length = 21 days), study drug discontinuation visit (up to approximately 18 months)
    End point values
    		 Onartuzumab+Erlotinib Placebo+Erlotinib
    Number of subjects analysed
    238
    241
    Units: units on a scale
    arithmetic mean (standard deviation)
        Screening: Alopecia (n=237,240)
    18 ± 31.5
    18.9 ± 32.3
        Screening: Coughing (n=238,237)
    35.6 ± 26.8
    38.3 ± 27.1
        Screening: Dysphagia (n=237,240)
    7.7 ± 18.9
    6.9 ± 16.1
        Screening: Dyspnoea (n=237,241)
    27.3 ± 23.3
    27.9 ± 23.3
        Screening: Haemoptysis (n=236,241)
    3.7 ± 12.9
    3.7 ± 12.9
        Screening: Pain in arm/shoulder (n=238,241)
    16.9 ± 27
    19.4 ± 28.3
        Screening: Pain in chest (n=237,241)
    19.8 ± 27.7
    15.1 ± 25.5
        Screening: Pain in other parts (n=234,238)
    28.9 ± 33.3
    27.9 ± 31.6
        Screening: Peripheral neuropathy (n=238,241)
    22.8 ± 28.7
    18.7 ± 28
        Screening: Sore mouth (n=236,241)
    6.6 ± 18.4
    5 ± 15.6
        Cycle 2 Day 1: Alopecia (n=196,205)
    8.3 ± 22.2
    9.9 ± 23.7
        Cycle 2 Day 1: Coughing (n=197,206)
    30.5 ± 23.8
    33.3 ± 27.5
        Cycle 2 Day 1: Dysphagia (n=198,205)
    8.6 ± 19.9
    8.8 ± 19.8
        Cycle 2 Day 1: Dyspnoea (n=197,206)
    28.8 ± 23.1
    26.9 ± 21
        Cycle 2 Day 1: Haemoptysis (n=197,206)
    3.6 ± 10.3
    3.4 ± 12.5
        Cycle 2 Day 1: Pain in Arm/Shoulder (n=197,204)
    14.6 ± 23.6
    15.8 ± 28
        Cycle 2 Day 1: Pain in chest (n=195,206)
    13.2 ± 22.3
    12.3 ± 21.3
        Cycle 2 Day 1: Pain in other parts (n=190,205)
    28.9 ± 30.4
    28.6 ± 32.9
        Cycle 2 Day 1: Peripheral neuropathy (n=196,206)
    26.4 ± 30.8
    19.6 ± 29.3
        Cycle 2 Day 1: Sore mouth (n=198,206)
    17.7 ± 28
    14.6 ± 24.5
        Cycle 4 Day 1: Alopecia (n=116,110)
    11.2 ± 22.4
    12.1 ± 22
        Cycle 4 Day 1: Coughing (n=118,111)
    30.5 ± 26
    27.6 ± 23.3
        Cycle 4 Day 1: Dysphagia (n=116,111)
    6.6 ± 15.4
    7.2 ± 18.8
        Cycle 4 Day 1: Dyspnoea (n=117,111)
    25.9 ± 21.8
    24.6 ± 19.3
        Cycle 4 Day 1: Haemoptysis (n=118,111)
    1.7 ± 7.4
    2.4 ± 9.8
        Cycle 4 Day 1: Pain in Arm/Shoulder (n=118,111)
    18.6 ± 26.3
    13.2 ± 23.9
        Cycle 4 Day 1: Pain in chest (n=118,110)
    14.4 ± 22
    10.6 ± 18
        Cycle 4 Day 1: Pain in other parts (n=117,111)
    28.5 ± 31
    22.2 ± 27.8
        Cycle 4 Day 1: Peripheral neuropathy (n=118,111)
    27.7 ± 30.3
    19.8 ± 26.7
        Cycle 4 Day 1: Sore mouth (n=118,111)
    12.7 ± 21.3
    10.5 ± 22.5
        Cycle 6 Day 1: Alopecia (n=76,77)
    16.7 ± 28.5
    17.3 ± 26.3
        Cycle 6 Day 1: Coughing (n=76,77)
    28.9 ± 26.3
    32 ± 22.6
        Cycle 6 Day 1: Dysphagia (n=77,78)
    7.4 ± 19.2
    4.3 ± 12.4
        Cycle 6 Day 1: Dyspnoea (n=77,78)
    29.5 ± 23.1
    22.6 ± 18.7
        Cycle 6 Day 1: Haemoptysis (n=77,78)
    4.8 ± 14
    4.3 ± 12.4
        Cycle 6 Day 1: Pain in Arm/Shoulder (n=77,77)
    20.8 ± 28.1
    9.1 ± 19.2
        Cycle 6 Day 1: Pain in chest (n=77,78)
    17.3 ± 22.7
    11.5 ± 20
        Cycle 6 Day 1: Pain in other parts (n=75,75)
    24 ± 28.8
    23.1 ± 28.5
        Cycle 6 Day 1: Peripheral neuropathy (n=76,78)
    26.3 ± 31.9
    23.9 ± 27.9
        Cycle 6 Day 1: Sore mouth (n=76,78)
    14.5 ± 22.7
    8.1 ± 16.3
        Cycle 8 Day 1: Alopecia (n=41,54)
    13.8 ± 24.7
    13 ± 25.4
        Cycle 8 Day 1: Coughing (n=41,53)
    25.2 ± 20.8
    29.6 ± 25
        Cycle 8 Day 1: Dysphagia (n=41,54)
    9.8 ± 18.6
    5.6 ± 14.1
        Cycle 8 Day 1: Dyspnoea (n=41,53)
    25.7 ± 21.4
    19.5 ± 18.7
        Cycle 8 Day 1: Haemoptysis (n=41,54)
    1.6 ± 7.3
    4.3 ± 13
        Cycle 8 Day 1: Pain in Arm/Shoulder (n=40,54)
    18.3 ± 28.2
    11.7 ± 21.6
        Cycle 8 Day 1: Pain in chest (n=41,54)
    17.9 ± 24.8
    8 ± 17.1
        Cycle 8 Day 1: Pain in other parts (n=40,54)
    25 ± 32.7
    22.2 ± 28.2
        Cycle 8 Day 1: Peripheral neuropathy (n=40,53)
    26.7 ± 32.2
    18.9 ± 24
        Cycle 8 Day 1: Sore mouth (n=41,54)
    4.9 ± 11.9
    7.4 ± 14
        Cycle 10 Day 1: Alopecia (n=26,34)
    11.5 ± 24.8
    16.7 ± 27.5
        Cycle 10 Day 1: Coughing (n=27,34)
    18.5 ± 16.9
    25.5 ± 18.5
        Cycle 10 Day 1: Dysphagia (n=27,34)
    7.4 ± 14.1
    3.9 ± 10.9
        Cycle 10 Day 1: Dyspnoea (n=27,34)
    23.3 ± 16.7
    18.6 ± 17
        Cycle 10 Day 1: Haemoptysis (n=27,34)
    0 ± 0
    1 ± 5.7
        Cycle 10 Day 1: Pain in Arm/Shoulder (n=27,33)
    7.4 ± 16.9
    16.2 ± 29
        Cycle 10 Day 1: Pain in chest (n=27,34)
    13.6 ± 24.9
    6.9 ± 16
        Cycle 10 Day 1: Pain in other parts (n=27,32)
    30.9 ± 35.7
    18.8 ± 23.9
        Cycle 10 Day 1: Peripheral neuropathy (n=27,34)
    24.7 ± 32.8
    18.6 ± 24.9
        Cycle 10 Day 1: Sore mouth (n=27,34)
    11.1 ± 18.5
    6.9 ± 13.7
        Cycle 12 Day 1: Alopecia (n=17,22)
    7.8 ± 25.1
    12.1 ± 26.3
        Cycle 12 Day 1: Coughing (n=17,22)
    11.8 ± 20.2
    30.3 ± 28.9
        Cycle 12 Day 1: Dysphagia (n=17,22)
    3.9 ± 11.1
    1.5 ± 7.1
        Cycle 12 Day 1: Dyspnoea (n=17,22)
    15.7 ± 13.1
    14.6 ± 17.3
        Cycle 12 Day 1: Haemoptysis (n=17,22)
    0 ± 0
    1.5 ± 7.1
        Cycle 12 Day 1: Pain in Arm/Shoulder (n=17,22)
    19.6 ± 26.5
    19.7 ± 24.5
        Cycle 12 Day 1: Pain in chest (n=17,21)
    7.8 ± 14.6
    7.9 ± 18
        Cycle 12 Day 1: Pain in other parts (n=16,22)
    22.9 ± 29.1
    19.7 ± 26.5
        Cycle 12 Day 1: Peripheral neuropathy (n=17,22)
    23.5 ± 32.8
    19.7 ± 24.5
        Cycle 12 Day 1: Sore mouth (n=17,22)
    9.8 ± 19.6
    3 ± 9.8
        Cycle 14 Day 1: Alopecia (n=9,10)
    14.8 ± 33.8
    16.7 ± 23.6
        Cycle 14 Day 1: Coughing (n=9,10)
    18.5 ± 24.2
    26.7 ± 21.1
        Cycle 14 Day 1: Dysphagia (n=9,10)
    7.4 ± 14.7
    6.7 ± 14.1
        Cycle 14 Day 1: Dyspnoea (n=9,10)
    22.2 ± 17.6
    27.8 ± 27.8
        Cycle 14 Day 1: Haemoptysis (n=9,10)
    0 ± 0
    6.7 ± 21.1
        Cycle 14 Day 1: Pain in Arm/Shoulder (n=9,10)
    22.2 ± 16.7
    16.7 ± 23.6
        Cycle 14 Day 1: Pain in chest (n=9,10)
    3.7 ± 11.1
    13.3 ± 23.3
        Cycle 14 Day 1: Pain in other parts (n=9,9)
    33.3 ± 28.9
    14.8 ± 24.2
        Cycle 14 Day 1: Peripheral neuropathy (n=9,10)
    40.7 ± 36.4
    16.7 ± 23.6
        Cycle 14 Day 1: Sore mouth (n=9,10)
    7.4 ± 14.7
    10 ± 22.5
        Cycle 16 Day 1: Alopecia (n=4,5)
    16.7 ± 33.3
    20 ± 29.8
        Cycle 16 Day 1: Coughing (n=4,5)
    16.7 ± 19.2
    26.7 ± 14.9
        Cycle 16 Day 1: Dysphagia (n=4,5)
    0 ± 0
    20 ± 18.3
        Cycle 16 Day 1: Dyspnoea (n=4,5)
    22.2 ± 18.1
    24.4 ± 12.2
        Cycle 16 Day 1: Haemoptysis (n=4,5)
    0 ± 0
    13.3 ± 18.3
        Cycle 16 Day 1: Pain in Arm/Shoulder (n=3,5)
    11.1 ± 19.2
    13.3 ± 18.3
        Cycle 16 Day 1: Pain in chest (n=4,5)
    0 ± 0
    13.3 ± 18.3
        Cycle 16 Day 1: Pain in other parts (n=3,5)
    66.7 ± 57.7
    20 ± 29.8
        Cycle 16 Day 1: Peripheral neuropathy (n=4,5)
    66.7 ± 38.5
    0 ± 0
        Cycle 16 Day 1: Sore mouth (n=4,5)
    25 ± 16.7
    0 ± 0
        Cycle 18 Day 1: Alopecia (n=0,3)
    99999 ± 99999
    11.1 ± 19.2
        Cycle 18 Day 1: Coughing (n=0,3)
    99999 ± 99999
    22.2 ± 19.2
        Cycle 18 Day 1: Dysphagia (n=0,3)
    99999 ± 99999
    11.1 ± 19.2
        Cycle 18 Day 1: Dyspnoea (n=0,3)
    99999 ± 99999
    25.9 ± 23.1
        Cycle 18 Day 1: Haemoptysis (n=0,3)
    99999 ± 99999
    11.1 ± 19.2
        Cycle 18 Day 1: Pain in Arm/Shoulder (n=0,3)
    99999 ± 99999
    11.1 ± 19.2
        Cycle 18 Day 1: Pain in chest (n=0,3)
    99999 ± 99999
    0 ± 0
        Cycle 18 Day 1: Pain in other parts (n=0,3)
    99999 ± 99999
    0 ± 0
        Cycle 18 Day 1: Peripheral neuropathy (n=0,3)
    99999 ± 99999
    0 ± 0
        Cycle 18 Day 1: Sore mouth (n=0,3)
    99999 ± 99999
    11.1 ± 19.2
        Cycle 20 Day 1: Alopecia (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 20 Day 1: Coughing (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 20 Day 1: Dysphagia (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 20 Day 1: Dyspnoea (n=0,1)
    99999 ± 99999
    44.4 ± 99999
        Cycle 20 Day 1: Haemoptysis (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 20 Day 1: Pain in Arm/Shoulder (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 20 Day 1: Pain in chest (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 20 Day 1: Pain in other parts (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 20 Day 1: Peripheral neuropathy (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 20 Day 1: Sore mouth (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 22 Day 1: Alopecia (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 22 Day 1: Coughing (n=0,1)
    99999 ± 99999
    66.7 ± 99999
        Cycle 22 Day 1: Dysphagia (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 22 Day 1: Dyspnoea (n=0,1)
    99999 ± 99999
    44.4 ± 99999
        Cycle 22 Day 1: Haemoptysis (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Cycle 22 Day 1: Pain in Arm/Shoulder (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 22 Day 1: Pain in chest (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 22 Day 1: Pain in other parts (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 22 Day 1: Peripheral neuropathy (n=0,1)
    99999 ± 99999
    0 ± 99999
        Cycle 22 Day 1: Sore mouth (n=0,1)
    99999 ± 99999
    33.3 ± 99999
        Drug discontinuation (DD): Alopecia (n=132,137)
    18.7 ± 30.1
    10.9 ± 22.5
        DD: Coughing (n=132,137)
    38.1 ± 26.7
    42.6 ± 31
        DD: Dysphagia (n=130,137)
    14.1 ± 26.2
    11.4 ± 22.3
        DD: Dyspnoea (n=131,136)
    39.5 ± 25.6
    35.7 ± 27.7
        DD: Haemoptysis (n=132,137)
    5.1 ± 15.1
    4.9 ± 16.9
        DD: Pain in Arm/Shoulder (n=131,137)
    20.1 ± 28.8
    21.9 ± 30.1
        DD: Pain in chest (n=132,137)
    21.7 ± 29.1
    19 ± 26.8
        DD: Pain in other parts (n=130,134)
    35.1 ± 34.8
    31.6 ± 34
        DD: Peripheral neuropathy (n=131,137)
    25.4 ± 28.6
    17 ± 26.5
        DD: Sore mouth (n=132,136)
    12.1 ± 24.5
    12.5 ± 21.1
        Unscheduled (Uns): Alopecia (n=6,1)
    11.1 ± 17.2
    0 ± 99999
        Uns: Coughing (n=6,1)
    44.4 ± 27.2
    33.3 ± 99999
        Uns: Dysphagia (n=6,1)
    22.2 ± 17.2
    0 ± 99999
        Uns: Dyspnoea (n=6,1)
    33.3 ± 25.3
    55.6 ± 99999
        Uns: Haemoptysis (n=6,1)
    0 ± 0
    33.3 ± 99999
        Uns: Pain in Arm/Shoulder (n=6,1)
    27.8 ± 25.1
    33.3 ± 99999
        Uns: Pain in chest (n=6,1)
    22.2 ± 27.2
    0 ± 99999
        Uns: Pain in other parts (n=5,1)
    33.3 ± 33.3
    66.7 ± 99999
        Uns: Peripheral neuropathy (n=6,1)
    44.4 ± 45.5
    33.3 ± 99999
        Uns: Sore mouth (n=6,1)
    11.1 ± 17.2
    0 ± 99999
    No statistical analyses for this end point

    Secondary: Onartuzumab Serum Concentrations

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    End point title
    		 Onartuzumab Serum Concentrations [1]
    End point description
    C1D1=Cycle 1 Day 1; C2D1=Cycle 2 Day 1; C4D1=Cycle 4 Day 1. Number of subjects analyzed=number of participants evaluable for this end point. "n" represents number of participants evaluable at the specified time point. When data was not available, the mean (standard deviation) was reported as 99999±99999.
    End point type
    Secondary
    End point timeframe
    1 hour pre-onartuzumab (Pr-O) infusion on Day 1 of Cycles 1, 2, and 4, 1 hour post-onartuzumab (Po-O) infusion on Day 1 of Cycle 1 (cycle length = 21 days and duration of infusion = 60 minutes), End of treatment (up to approximately 18 months)
    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: Onartuzumab serum concentration assessment is applicable only in "Onartuzumab + Erlotinib" and only this arm is selected.
    End point values
    		 Onartuzumab+Erlotinib
    Number of subjects analysed
    240
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        C1D1: 1 hour Pr-O (n=240)
    99999 ± 99999
        C1D1: 1 hour Po-O (n=235)
    382 ± 201
        C2D1: 1 hour Pr-O (n=202)
    36.2 ± 13.9
        C4D1: 1 hour Po-O (n=125)
    62 ± 28.6
        End of treatment (n=137)
    43.1 ± 32.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 20 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo+Erlotinib
    Reporting group description
    		 Participants received onartuzumab matching placebo on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg orally QD from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Reporting group title
    Onartuzumab+Erlotinib
    Reporting group description
    		 Participants received onartuzumab 15 mg/kg IV infusion on Day 1 of every cycle of 3 weeks along with erlotinib 150 mg orally QD from Day 1, Cycle 1 until there was evidence of disease progression, death, or unacceptable toxicity, whichever occurred first.

    Serious adverse events
    		 Placebo+Erlotinib Onartuzumab+Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 244 (33.20%)
    89 / 248 (35.89%)
         number of deaths (all causes)
    11
    17
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Axillary vein thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicose ulceration
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 244 (0.00%)
    4 / 248 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 244 (0.82%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oedema
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 244 (1.64%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 244 (2.05%)
    6 / 248 (2.42%)
         occurrences causally related to treatment / all
    1 / 7
    2 / 6
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 244 (1.23%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 244 (0.41%)
    5 / 248 (2.02%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 244 (0.00%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 244 (1.23%)
    8 / 248 (3.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 244 (0.82%)
    3 / 248 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Cardiac output decreased
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    4 / 244 (1.64%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (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
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dysphagia
         subjects affected / exposed
    4 / 244 (1.64%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal perforation
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Melaena
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 244 (2.05%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 244 (0.82%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 244 (0.82%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nephrolithiasis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 244 (0.00%)
    4 / 248 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute endocarditis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Folliculitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    10 / 244 (4.10%)
    7 / 248 (2.82%)
         occurrences causally related to treatment / all
    0 / 10
    2 / 7
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Pulmonary sepsis
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 244 (0.00%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Scrotal abscess
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 244 (0.41%)
    2 / 248 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 244 (0.41%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 244 (1.23%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 244 (0.82%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 244 (0.41%)
    4 / 248 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 244 (0.41%)
    0 / 248 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 244 (0.00%)
    1 / 248 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo+Erlotinib Onartuzumab+Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    225 / 244 (92.21%)
    228 / 248 (91.94%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 244 (3.69%)
    19 / 248 (7.66%)
         occurrences all number
    10
    22
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 244 (2.46%)
    18 / 248 (7.26%)
         occurrences all number
    6
    24
    Blood bilirubin increased
         subjects affected / exposed
    13 / 244 (5.33%)
    4 / 248 (1.61%)
         occurrences all number
    14
    4
    Weight decreased
         subjects affected / exposed
    32 / 244 (13.11%)
    18 / 248 (7.26%)
         occurrences all number
    32
    19
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 244 (4.51%)
    19 / 248 (7.66%)
         occurrences all number
    11
    22
    Dysgeusia
         subjects affected / exposed
    16 / 244 (6.56%)
    17 / 248 (6.85%)
         occurrences all number
    16
    17
    Headache
         subjects affected / exposed
    5 / 244 (2.05%)
    15 / 248 (6.05%)
         occurrences all number
    5
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    22 / 244 (9.02%)
    18 / 248 (7.26%)
         occurrences all number
    28
    21
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    23 / 244 (9.43%)
    24 / 248 (9.68%)
         occurrences all number
    24
    29
    Chest pain
         subjects affected / exposed
    14 / 244 (5.74%)
    15 / 248 (6.05%)
         occurrences all number
    16
    15
    Fatigue
         subjects affected / exposed
    76 / 244 (31.15%)
    69 / 248 (27.82%)
         occurrences all number
    89
    80
    Mucosal inflammation
         subjects affected / exposed
    12 / 244 (4.92%)
    16 / 248 (6.45%)
         occurrences all number
    12
    16
    Oedema peripheral
         subjects affected / exposed
    20 / 244 (8.20%)
    59 / 248 (23.79%)
         occurrences all number
    22
    73
    Pyrexia
         subjects affected / exposed
    27 / 244 (11.07%)
    17 / 248 (6.85%)
         occurrences all number
    29
    19
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    10 / 244 (4.10%)
    17 / 248 (6.85%)
         occurrences all number
    10
    21
    Abdominal pain upper
         subjects affected / exposed
    14 / 244 (5.74%)
    13 / 248 (5.24%)
         occurrences all number
    14
    16
    Constipation
         subjects affected / exposed
    34 / 244 (13.93%)
    30 / 248 (12.10%)
         occurrences all number
    40
    32
    Diarrhoea
         subjects affected / exposed
    116 / 244 (47.54%)
    100 / 248 (40.32%)
         occurrences all number
    169
    149
    Nausea
         subjects affected / exposed
    62 / 244 (25.41%)
    68 / 248 (27.42%)
         occurrences all number
    73
    88
    Stomatitis
         subjects affected / exposed
    23 / 244 (9.43%)
    23 / 248 (9.27%)
         occurrences all number
    27
    28
    Vomiting
         subjects affected / exposed
    37 / 244 (15.16%)
    38 / 248 (15.32%)
         occurrences all number
    46
    53
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    55 / 244 (22.54%)
    36 / 248 (14.52%)
         occurrences all number
    57
    39
    Dyspnoea
         subjects affected / exposed
    49 / 244 (20.08%)
    51 / 248 (20.56%)
         occurrences all number
    54
    59
    Epistaxis
         subjects affected / exposed
    12 / 244 (4.92%)
    18 / 248 (7.26%)
         occurrences all number
    12
    18
    Haemoptysis
         subjects affected / exposed
    18 / 244 (7.38%)
    13 / 248 (5.24%)
         occurrences all number
    24
    14
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    14 / 244 (5.74%)
    9 / 248 (3.63%)
         occurrences all number
    14
    9
    Dermatitis acneiform
         subjects affected / exposed
    64 / 244 (26.23%)
    79 / 248 (31.85%)
         occurrences all number
    75
    104
    Dry skin
         subjects affected / exposed
    53 / 244 (21.72%)
    51 / 248 (20.56%)
         occurrences all number
    55
    63
    Pruritus
         subjects affected / exposed
    32 / 244 (13.11%)
    30 / 248 (12.10%)
         occurrences all number
    43
    37
    Rash
         subjects affected / exposed
    92 / 244 (37.70%)
    95 / 248 (38.31%)
         occurrences all number
    116
    126
    Psychiatric disorders
    Depression
         subjects affected / exposed
    7 / 244 (2.87%)
    14 / 248 (5.65%)
         occurrences all number
    7
    14
    Insomnia
         subjects affected / exposed
    18 / 244 (7.38%)
    22 / 248 (8.87%)
         occurrences all number
    21
    23
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    18 / 244 (7.38%)
    28 / 248 (11.29%)
         occurrences all number
    19
    33
    Muscle spasms
         subjects affected / exposed
    9 / 244 (3.69%)
    16 / 248 (6.45%)
         occurrences all number
    9
    22
    Muscular weakness
         subjects affected / exposed
    6 / 244 (2.46%)
    14 / 248 (5.65%)
         occurrences all number
    7
    18
    Pain in extremity
         subjects affected / exposed
    12 / 244 (4.92%)
    16 / 248 (6.45%)
         occurrences all number
    14
    18
    Infections and infestations
    Paronychia
         subjects affected / exposed
    25 / 244 (10.25%)
    27 / 248 (10.89%)
         occurrences all number
    34
    27
    Urinary tract infection
         subjects affected / exposed
    13 / 244 (5.33%)
    8 / 248 (3.23%)
         occurrences all number
    17
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    78 / 244 (31.97%)
    72 / 248 (29.03%)
         occurrences all number
    91
    80
    Dehydration
         subjects affected / exposed
    16 / 244 (6.56%)
    10 / 248 (4.03%)
         occurrences all number
    19
    12
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 244 (4.10%)
    43 / 248 (17.34%)
         occurrences all number
    10
    46
    Hypokalaemia
         subjects affected / exposed
    16 / 244 (6.56%)
    16 / 248 (6.45%)
         occurrences all number
    20
    20

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2012
    A futility boundary was added to the interim analysis, allowing for early termination of the trial if it became clear that a statistically significant difference by the end of study would be improbable. The total number of events for the final analysis was revised to 364 (from 363) and the number of participants was revised to 490 (from 480). The analysis of the secondary efficacy endpoints was revised from a two-sided 5% significance level to a one-sided 2.5% significance level. Per a request made by the European Voluntary Harmonization Procedure, it was added that vital signs to be collected at baseline and each subsequent visit, and regular urinalysis was also added. Procedures for potential emergency unblinding were included. The use of systemic corticosteroids was added for the treatment of chronic obstructive pulmonary disease.
    22 May 2014
    The protocol was amended after the protocol-specified interim analysis for efficacy and futility was performed. This interim analysis demonstrated that participants in the onartuzumab arm did not have longer OS (primary endpoint), longer PFS (secondary endpoint), or an improved objective response rate (ORR) compared with participants in the placebo arm. This amendment reduced the protocol-specified assessments for participants who were either on active study treatment (onartuzumab arm or erlotinib alone) or in the survival follow-up period. Additionally, the end of study was defined, and the potential provision for drug supply through a program-wide independent protocol was included to allow participants from this and other onartuzumab studies to continue receiving treatment.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    28 Jan 2016
    A decision was made by the sponsor to discontinue further clinical development of onartuzumab.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The clinical development of onartuzumab was terminated as per decision made by sponsor primarily due to limited efficacy observed in the conduct of this study and was not based on safety-related issues.
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