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    Clinical Trial Results:
    Phase II, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

    Summary
    EudraCT number
    2010-022509-17
    Trial protocol
    PT  
    Global end of trial date
    29 Sep 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Oct 2018
    First version publication date
    12 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ML25434
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01260181
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, 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
    29 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This single arm, open-label study evaluated the efficacy and safety of erlotinib (Tarceva) in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Mar 2011
    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
    Portugal: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    13
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 30 subjects were included in the study.

    Pre-assignment
    Screening details
    A total of 216 subjets were screened for this study in Portugal. From those, 186 were screening failures due to not complying with inclusion/exclusion criteria or at subjects decision. Thirty subjects were enrolled to the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Erlotinib
    Arm description
    Subjects received erlotinib 150 millgrams (mg) orally daily until disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Erlotinib 150 mg tablet was taken orally daily.

    Number of subjects in period 1
    Erlotinib
    Started
    30
    Completed
    29
    Not completed
    1
         Decision of Investigator
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Subjects received erlotinib 150 millgrams (mg) orally daily until disease progression.

    Reporting group values
    Erlotinib Total
    Number of subjects
    30 30
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    13 13
        From 65-84 years
    17 17
        85 years and over
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    66.33 ± 9.21 -
    Sex: Female, Male
    Units: Subjects
        Female
    24 24
        Male
    6 6
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0
        Asian
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    0 0
        White
    0 0
        More than one race
    0 0
        Unknown or Not Reported
    30 30

    End points

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    End points reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Subjects received erlotinib 150 millgrams (mg) orally daily until disease progression.

    Primary: Percentage of Subjects with Objective Response (Complete Response [CR]/Partial Response [PR]) Based on Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

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    End point title
    Percentage of Subjects with Objective Response (Complete Response [CR]/Partial Response [PR]) Based on Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 [1]
    End point description
    Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
    End point type
    Primary
    End point timeframe
    Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])
    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 was a one-armed study so no statistical analyses were done.
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: percentage of subjects
        number (confidence interval 95%)
    63.3 (46.1 to 80.6)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Based on CT or MRI According to RECIST v 1.1

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    End point title
    Progression Free Survival (PFS) Based on CT or MRI According to RECIST v 1.1
    End point description
    Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: weeks
        median (confidence interval 95%)
    40 (31 to 63)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline up to 5 years
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: weeks
        median (confidence interval 95%)
    83 (56 to 125)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events

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    End point title
    Percentage of Subjects with Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Baseline up to 5 years
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: percentage of subjects
    29
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Epidermal Growth Factor Receptor (EGFR) Mutation in Study Population

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    End point title
    Percentage of Subjects with Epidermal Growth Factor Receptor (EGFR) Mutation in Study Population
    End point description
    Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.
    End point type
    Secondary
    End point timeframe
    Screening (21 days prior to Day 1)
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: percentage of subjects
        Exon 19 mutation|
    40
        Exon 21 mutation|
    60
    No statistical analyses for this end point

    Secondary: Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator

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    End point title
    Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator
    End point description
    The response duration was defined as the time of initial response (complete response (CR) /partial response (PR) whichever is first recorded) until documented disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
    End point type
    Secondary
    End point timeframe
    Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])
    End point values
    Erlotinib
    Number of subjects analysed
    30
    Units: weeks
        median (confidence interval 95%)
    41.5 (32 to 63)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    5 years
    Adverse event reporting additional description
    The safety population was identical to the ITT population, which included all subjects enrolled in the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Erlotinib
    Reporting group description
    Subjects received erlotinib 150 millgrams (mg) orally daily until disease progression.

    Serious adverse events
    Erlotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 30 (26.67%)
         number of deaths (all causes)
    4
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary Embolism
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal Perforation
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pelvic Infection
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Erlotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 30 (96.67%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    8
    Oedema Peripheral
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Asthenia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Influenza Like Illness
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Pain
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Depression
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    5
    Neutrophil Count Increased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Weight Decreased
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Dyspnoea
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    7
    Haemoptysis
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Nasal Congestion
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Productive Cough
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 30 (13.33%)
         occurrences all number
    4
    Dizziness
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Eye disorders
    Dry Eye
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Blepharitis
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Cataract
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 30 (50.00%)
         occurrences all number
    19
    Constipation
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Stomatitis
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    6
    Dyspepsia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Odynophagia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Abdominal Pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Dermatitis Acneiform
         subjects affected / exposed
    19 / 30 (63.33%)
         occurrences all number
    30
    Rash Maculo-Papular
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    11
    Alopecia
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Acne
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Erythema
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    7
    Pain in Extremity
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    4
    Bone Pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    3
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Neck Pain
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    8 / 30 (26.67%)
         occurrences all number
    12
    Hyperglycaemia
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    5
    Hypomagnesaemia
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Infections and infestations
    Paronychia
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    13
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    7
    Eye Infection
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Conjunctivitis
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2011
    Protocol was amended to extend the recruitment period and study duration so that the sample size aimed for the study (30) would be achieved.
    12 Feb 2014
    Protocol was amended to include an interim analysis. This interim analysis allowed a preliminary understanding about the clinical benefits of erlotinib in this population and compared it with published studies that were conducted in the Caucasian international population. Also to allow the basal characterization of this population, specially the rate of EGFR mutation and the histological type.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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