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    Clinical Trial Results:
    An open-label phase II trial of erlotinib and bevacizumab in patients with advanced non-small cell lung cancer and activating EGFR mutations

    Summary
    EudraCT number
    		 2011-004481-15
    Trial protocol
    		 ES   IE   FR   GR   GB   IT   DE  
    Global end of trial date
    31 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2020
    First version publication date
    07 Feb 2020
    Other versions
    Summary report(s)
    		 Publication_Rosell et al_LancetRM_2017_DOI: 10.1016/S2213-2600(17)30129-7

    Trial information

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    Trial identification
    Sponsor protocol code
    ETOP2-11/MO27911
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01562028
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    European Thoracic Oncology Platform (ETOP)
    Sponsor organisation address
    Effingerstrasse 40, Bern, Switzerland, 3008
    Public contact
    ETOP Coordinating Office, ETOP, +41 31 511 94 00, belief@etop-eu.org
    Scientific contact
    ETOP Coordinating Office, ETOP, +41 31 511 94 00, belief@etop-eu.org
    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
    22 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine progression free survival (PFS) of patients with advanced non-squamous NSCLC harbouring at diagnosis EGFR mutations with and without T790M mutation, treated with the combination of erlotinib and bevacizumab. Hypotheses of interest: When treated with bevacizumab and erlotinib a. Median PFS increases to 18 months for patients with EGFR T790M mutation b. Median PFS is approximately 18 months or more in patients without EGFR T790M mutation.
    Protection of trial subjects
    Trial subjects are closely monitored during the entire duration of the trial by the participating investigators. For safety purposes any adverse events occurred from enrolment of a trial subject until 30 days after treatment discontinuation need to be reported. In case of adverse events and treatment-related toxicities management guidance have been provided in the study protocol to treat trial subjects in adequately manner. Precautions and warnings about the use of the study drug are provided in the trial subject information sheet to ensure that study drug is correctly used in order to avoid unnecessary adverse reactions and in addition to ensure that in case of an adverse event the study patient contacts the investigator for appropriate measures. The safety and efficacy of the trial treatment have been regularly reviewed by the ETOP IDMC (independent data monitoring committee) at their semi-annual meetings to safeguard the interest and safety of the patients in the trial and to ensure the scientific integrity of the trial. Additionally, the risk/benefit ratio have been regularly evaluated by the ETOP Steering Committee on a semi-annual basis. Technical and organisational controls (including physical, electronic and managerial measures) are in place to protect personal data and integrity of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 May 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
    Switzerland: 41
    Country: Number of subjects enrolled
    Spain: 46
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    109
    EEA total number of subjects
    68
    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)
    51
    From 65 to 84 years
    58
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between June 11, 2012 and Oct 28, 2014, 109 eligible patients were enrolled in 29 centers of eight European countries (Spain, Switzerland, UK, Greece, Italy, Ireland, France and Germany). All patients were included in the efficacy analysis.

    Pre-assignment
    Screening details
    		 Three patients hadn't received any dose of trial treatment. The safety analysis was conducted based on 106 patients (safety cohort).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 T790M Positive
    Arm description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), with T790M, treated with erlotinib and bevacizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tarceva
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will be treated with erlotinib, 150 mg p.o., daily.

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 21 day cycle.

    Arm title
    		 T790M Negative
    Arm description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), without T790M, treated with erlotinib and bevacizumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tarceva
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients will be treated with erlotinib, 150 mg p.o., daily.

    Investigational medicinal product name
    Avastin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 21 day cycle.

    Number of subjects in period 1
    		T790M Positive T790M Negative
    Started
    37
    72
    Completed
    34
    70
    Not completed
    3
    2
         Consent withdrawn by subject
    1
    1
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    T790M Positive
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), with T790M, treated with erlotinib and bevacizumab.

    Reporting group title
    T790M Negative
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), without T790M, treated with erlotinib and bevacizumab.

    Reporting group values
    		 T790M Positive T790M Negative Total
    Number of subjects
    		 37 72 109
    Age categorical
    Age as continuous characteristic only
    Units: Subjects
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 69.5 (62.3 to 74.0) 63 (53.4 to 71.2) -
    Gender categorical
    Units: Subjects
        Female
    		 25 42 67
        Male
    		 12 30 42
    Smoking status
    Units: Subjects
        Current smoker
    		 0 7 7
        Former smoker
    		 10 20 30
        Never smoked
    		 27 45 72
    Histological diagnosis
    Units: Subjects
        Adenocarcinoma
    		 34 59 93
        Adenosquamous carcinoma
    		 1 1 2
        Not otherwise specified
    		 1 2 3
        Unknown
    		 1 10 11
    ECOG performance status
    ECOG Performance status scaling: PS 0:Fully active, able to carry on all pre-disease performance without restriction. PS 1:Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work. PS 2:Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. PS 3:Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. PS 4:Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
    Units: Subjects
        PS 0
    		 17 36 53
        PS 1
    		 18 32 50
        PS 2
    		 2 4 6
    Brain metastasis
    Units: Subjects
        Yes
    		 7 14 21
        No
    		 30 58 88
    Type of EGFR mutation
    Units: Subjects
        Deletion of exon 19
    		 23 47 70
        L858R mutation in exon 21
    		 14 25 39
    BRCA1 mRNA expression
    Units: Subjects
        Low (<9.2)
    		 10 13 23
        High (≥9.2)
    		 10 13 23
        No material or no value
    		 17 46 63
    AEG1 mRNA expression
    Units: Subjects
        Low (<1)
    		 11 20 31
        High (≥1)
    		 12 18 30
        No material or no value
    		 14 34 48

    End points

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    End points reporting groups
    Reporting group title
    T790M Positive
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), with T790M, treated with erlotinib and bevacizumab.

    Reporting group title
    T790M Negative
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), without T790M, treated with erlotinib and bevacizumab.

    Primary: Progression Free Survival

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    End point title
    		 Progression Free Survival [1]
    End point description
    Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Primary
    End point timeframe
    From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.
    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: In the cohort of T790M positive pts, among the first 35 pts, 23 reached 12 months without PFS event and thus, according to Simon’s two-stage design, this cohort showed that erlotinib plus bevacizumab is a promising treatment. In the cohort of T790M negative pts, median PFS was 10.5 months (95% CI: 9.4-14.2) and 12-month PFS rate 48% (95% CI: 36-59), and we could not reject the null hypothesis of 12-month PFS rate<=50%, versus the alternative of rate >50% evaluated at rate=65% (Fleming's design).
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37 [2]
    72
    Units: months
        median (confidence interval 95%)
    16 (12.7 to 16)
    10.5 (9.4 to 14.2)
    Notes
    [2] - The upper 95% limit is not estimable, so indicatively we present the estimation of the median.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Time from the date of enrollment until death from any cause.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment until death, assessed up to 48 months.
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37 [3]
    72
    Units: months
        median (confidence interval 95%)
    18.6 (18.6 to 18.6)
    28.2 (21.4 to 41.8)
    Notes
    [3] - Median is not reached & upper limit is not estimable, so indicatively we present the lower limit.
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment until discontinuation of treatment, assessed up to 48 months.
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37
    72
    Units: months
        median (confidence interval 95%)
    13.4 (5.6 to 19.6)
    8.3 (6.3 to 9.8)
    No statistical analyses for this end point

    Secondary: Objective Response

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    End point title
    		 Objective Response
    End point description
    Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.
    End point type
    Secondary
    End point timeframe
    Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37
    72
    Units: participants
        Complete Response
    3
    3
        Partial Response
    24
    54
        Stable Disease
    8
    9
        Progressive Disease
    1
    3
        Non-Evaluable
    1
    3
    No statistical analyses for this end point

    Secondary: Disease Control

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    End point title
    		 Disease Control
    End point description
    Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.
    End point type
    Secondary
    End point timeframe
    Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37
    72
    Units: paticipants
        Disease Control
    35
    66
        No Disease Control
    2
    6
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
    End point type
    Secondary
    End point timeframe
    Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    37 [4]
    72
    Units: months
        median (confidence interval 95%)
    14.7 (14.7 to 14.7)
    12 (8.2 to 20.2)
    Notes
    [4] - Median is not reached & upper limit is not estimable, so indicatively we present the lower limit.
    No statistical analyses for this end point

    Secondary: Adverse Events

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    End point title
    		 Adverse Events
    End point description
    Adverse events graded according to NCI CTCAE V4.
    End point type
    Secondary
    End point timeframe
    Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).
    End point values
    		 T790M Positive T790M Negative
    Number of subjects analysed
    36 [5]
    70 [6]
    Units: participants
        Experienced AE/SAE
    36
    69
        No AE/SAE
    0
    1
        Experienced SAE
    12
    19
    Notes
    [5] - One patient never started treatment (lost to follow-up).
    [6] - Two patients never started treatment (one due to withdrawal and one patient was lost to follow-up).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).
    Adverse event reporting additional description
    One patient from the T790 positive arm never started treatment (lost to follow-up). Two patients from the T790 negative arm never started treatment (one lost to follow-up and one withdrawal).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    T790M Positive
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), with T790M, treated with erlotinib (150 mg p.o., daily) and bevacizumab (15 mg/kg i.v. on day 1 of each 21 day cycle).

    Reporting group title
    T790M Negative
    Reporting group description
    		 Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), without T790M, treated with erlotinib (150 mg p.o., daily) and bevacizumab (15 mg/kg i.v. on day 1 of each 21 day cycle).

    Serious adverse events
    		 T790M Positive T790M Negative
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 36 (33.33%)
    19 / 70 (27.14%)
         number of deaths (all causes)
    13
    28
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thromboembolic event
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 70 (4.29%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Serum amylase increased
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (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 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disturbance
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic perforation
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal hemorrhage
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 70 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 70 (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 / 36 (2.78%)
    1 / 70 (1.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 70 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 T790M Positive T790M Negative
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 36 (100.00%)
    69 / 70 (98.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    33 / 36 (91.67%)
    62 / 70 (88.57%)
         occurrences all number
    33
    62
    Thromboembolic event
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Hematoma
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 70 (4.29%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 36 (63.89%)
    34 / 70 (48.57%)
         occurrences all number
    23
    34
    Pain
         subjects affected / exposed
    10 / 36 (27.78%)
    12 / 70 (17.14%)
         occurrences all number
    10
    12
    Edema limbs
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 70 (5.71%)
         occurrences all number
    5
    4
    Fever
         subjects affected / exposed
    3 / 36 (8.33%)
    5 / 70 (7.14%)
         occurrences all number
    3
    5
    Flu like symptoms
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 70 (5.71%)
         occurrences all number
    3
    4
    Other
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 70 (4.29%)
         occurrences all number
    3
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 36 (66.67%)
    30 / 70 (42.86%)
         occurrences all number
    24
    30
    Epistaxis
         subjects affected / exposed
    18 / 36 (50.00%)
    20 / 70 (28.57%)
         occurrences all number
    18
    20
    Dyspnea
         subjects affected / exposed
    12 / 36 (33.33%)
    18 / 70 (25.71%)
         occurrences all number
    12
    18
    Other
         subjects affected / exposed
    4 / 36 (11.11%)
    4 / 70 (5.71%)
         occurrences all number
    4
    4
    Voice alteration
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 70 (5.71%)
         occurrences all number
    5
    4
    Hoarseness
         subjects affected / exposed
    3 / 36 (8.33%)
    5 / 70 (7.14%)
         occurrences all number
    3
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 70 (10.00%)
         occurrences all number
    2
    7
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 70 (4.29%)
         occurrences all number
    2
    3
    Insomnia
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Investigations
    Alanine aminotransferase increase
         subjects affected / exposed
    8 / 36 (22.22%)
    21 / 70 (30.00%)
         occurrences all number
    8
    21
    Aspartate aminotransferase increase
         subjects affected / exposed
    7 / 36 (19.44%)
    21 / 70 (30.00%)
         occurrences all number
    7
    21
    Creatinine increased
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 70 (2.86%)
         occurrences all number
    3
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 70 (4.29%)
         occurrences all number
    1
    3
    Cardiac disorders
    Chest pain - cardiac
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 36 (22.22%)
    13 / 70 (18.57%)
         occurrences all number
    8
    13
    Dysgeusia
         subjects affected / exposed
    6 / 36 (16.67%)
    12 / 70 (17.14%)
         occurrences all number
    6
    12
    Dizziness
         subjects affected / exposed
    6 / 36 (16.67%)
    10 / 70 (14.29%)
         occurrences all number
    6
    10
    Paresthesia
         subjects affected / exposed
    3 / 36 (8.33%)
    6 / 70 (8.57%)
         occurrences all number
    3
    6
    Other
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Aphonia
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 70 (0.00%)
         occurrences all number
    4
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 70 (4.29%)
         occurrences all number
    1
    3
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 70 (5.71%)
         occurrences all number
    1
    4
    Other
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 70 (5.71%)
         occurrences all number
    0
    4
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    9 / 36 (25.00%)
    9 / 70 (12.86%)
         occurrences all number
    9
    9
    Other
         subjects affected / exposed
    5 / 36 (13.89%)
    7 / 70 (10.00%)
         occurrences all number
    5
    7
    Dry eye
         subjects affected / exposed
    3 / 36 (8.33%)
    5 / 70 (7.14%)
         occurrences all number
    3
    5
    Watering eyes
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 70 (1.43%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    30 / 36 (83.33%)
    55 / 70 (78.57%)
         occurrences all number
    30
    55
    Nausea
         subjects affected / exposed
    13 / 36 (36.11%)
    20 / 70 (28.57%)
         occurrences all number
    13
    20
    Mucositis oral
         subjects affected / exposed
    15 / 36 (41.67%)
    15 / 70 (21.43%)
         occurrences all number
    15
    15
    Abdominal pain
         subjects affected / exposed
    4 / 36 (11.11%)
    15 / 70 (21.43%)
         occurrences all number
    4
    15
    Constipation
         subjects affected / exposed
    8 / 36 (22.22%)
    12 / 70 (17.14%)
         occurrences all number
    8
    12
    Vomiting
         subjects affected / exposed
    7 / 36 (19.44%)
    1 / 70 (1.43%)
         occurrences all number
    7
    1
    Other
         subjects affected / exposed
    6 / 36 (16.67%)
    3 / 70 (4.29%)
         occurrences all number
    6
    3
    Hemorrhoids
         subjects affected / exposed
    4 / 36 (11.11%)
    5 / 70 (7.14%)
         occurrences all number
    4
    5
    Anal hemorrhage
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 70 (4.29%)
         occurrences all number
    4
    3
    Dry mouth
         subjects affected / exposed
    5 / 36 (13.89%)
    3 / 70 (4.29%)
         occurrences all number
    5
    3
    Oral hemorrhage
         subjects affected / exposed
    3 / 36 (8.33%)
    5 / 70 (7.14%)
         occurrences all number
    3
    5
    Dysphagia
         subjects affected / exposed
    4 / 36 (11.11%)
    2 / 70 (2.86%)
         occurrences all number
    4
    2
    Gastroesophageal reflux disease
         subjects affected / exposed
    2 / 36 (5.56%)
    5 / 70 (7.14%)
         occurrences all number
    2
    5
    Dyspepsia
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 70 (4.29%)
         occurrences all number
    1
    3
    Gastritis
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Hemorrhoidal hemorrhage
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Oral pain
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 70 (1.43%)
         occurrences all number
    2
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    28 / 36 (77.78%)
    55 / 70 (78.57%)
         occurrences all number
    28
    55
    Dry skin
         subjects affected / exposed
    17 / 36 (47.22%)
    20 / 70 (28.57%)
         occurrences all number
    17
    20
    Rash acneiform
         subjects affected / exposed
    10 / 36 (27.78%)
    13 / 70 (18.57%)
         occurrences all number
    10
    13
    Other
         subjects affected / exposed
    9 / 36 (25.00%)
    13 / 70 (18.57%)
         occurrences all number
    9
    13
    Alopecia
         subjects affected / exposed
    8 / 36 (22.22%)
    11 / 70 (15.71%)
         occurrences all number
    8
    11
    Pruritus
         subjects affected / exposed
    10 / 36 (27.78%)
    6 / 70 (8.57%)
         occurrences all number
    10
    6
    Erythema multiforme
         subjects affected / exposed
    6 / 36 (16.67%)
    6 / 70 (8.57%)
         occurrences all number
    6
    6
    Nail ridging
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 70 (4.29%)
         occurrences all number
    2
    3
    Nail discoloration
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 70 (1.43%)
         occurrences all number
    2
    1
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    3
    Skin ulceration
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    27 / 36 (75.00%)
    34 / 70 (48.57%)
         occurrences all number
    27
    34
    Hematuria
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 70 (5.71%)
         occurrences all number
    1
    4
    Other
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 70 (7.14%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    8 / 36 (22.22%)
    13 / 70 (18.57%)
         occurrences all number
    8
    13
    Back pain
         subjects affected / exposed
    4 / 36 (11.11%)
    15 / 70 (21.43%)
         occurrences all number
    4
    15
    Arthralgia
         subjects affected / exposed
    7 / 36 (19.44%)
    7 / 70 (10.00%)
         occurrences all number
    7
    7
    Pain in extremity
         subjects affected / exposed
    6 / 36 (16.67%)
    8 / 70 (11.43%)
         occurrences all number
    6
    8
    Myalgia
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 70 (8.57%)
         occurrences all number
    2
    6
    Other
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 70 (5.71%)
         occurrences all number
    1
    4
    Chest wall pain
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 70 (5.71%)
         occurrences all number
    1
    4
    Arthritis
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Infections and infestations
    Paronychia
         subjects affected / exposed
    8 / 36 (22.22%)
    8 / 70 (11.43%)
         occurrences all number
    8
    8
    Urinary tract infection
         subjects affected / exposed
    6 / 36 (16.67%)
    7 / 70 (10.00%)
         occurrences all number
    6
    7
    Upper respiratory infection
         subjects affected / exposed
    6 / 36 (16.67%)
    6 / 70 (8.57%)
         occurrences all number
    6
    6
    Other
         subjects affected / exposed
    5 / 36 (13.89%)
    5 / 70 (7.14%)
         occurrences all number
    5
    5
    Nail infection
         subjects affected / exposed
    3 / 36 (8.33%)
    6 / 70 (8.57%)
         occurrences all number
    3
    6
    Lung infection
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Mucosal infection
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 70 (4.29%)
         occurrences all number
    3
    3
    Bronchial infection
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 70 (2.86%)
         occurrences all number
    2
    2
    Rhinitis infective
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 70 (4.29%)
         occurrences all number
    1
    3
    Lip infection
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 70 (4.29%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    10 / 36 (27.78%)
    18 / 70 (25.71%)
         occurrences all number
    10
    18
    Other
         subjects affected / exposed
    4 / 36 (11.11%)
    7 / 70 (10.00%)
         occurrences all number
    4
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2013
    The protocol has been revised to add new safety information from the updated Investigators Brochure of bevacizumab. It also includes several other minor clarification and modifications. The following safety information for bevacizumab have been updated: - Addition of necrotizing fasciitis as a known adverse reaction of bevacizumab and the managment of this toxicity . - Further new safety information includes detailed clinical aspects of some known adverse events of bevacizumab. - Ovarian failure/fertility and arthralgia are also considered as known adverse reactions of bevacizumab. Additional modifications included in the protocol amendment 1 are: - Together with serum samples the collection of plasma samples have been added together - Additional exclusion criteria - Procedure for bevacizumab administration in case of delay - Treatment compliance for erlotinib which will be monitored by a patient diary - Additional criteria for discontinuing bevacizumab - Modified definitions of Serious Adverse Events (SAE) and of Adverse Events of Special Interest (AESI) for bevacizumab - Adapted procedure for blood collection, serum and plasma preparation - Updated baseline evaluations and evaluations after progression - Statistical update of sample size determination - Modified general criteria for termination of the trial - Clarification concerning the withdrawal of consent, quality assurance, protocol adherence, record retention and access rules to patient data

    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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