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BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC)

Sponsor
ETOP IBCSG Partners Foundation (Other)
Overall Status
Completed
CT.gov ID
NCT01562028
Collaborator
Spanish Lung Cancer Group (Other)
109
Enrollment
48
Locations
1
Arm
77
Duration (Months)
2.3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Rationale:

Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.

The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Objectives:

  1. To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. Primary endpoint: progression-free survival

  2. To evaluate the efficacy and tolerability of the combination

  3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival

  4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally

  5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab

Design:

This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. Patients will be stratified into two subgroups, with and without EGFR T790M mutation. The stratification will be done after the inclusion of patients.

Sample size: 102 patients

Study Design

Study Type:
Interventional
Actual Enrollment :
109 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations
Study Start Date :
Jun 1, 2012
Actual Primary Completion Date :
Oct 31, 2018
Actual Study Completion Date :
Oct 31, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Erlotinib plus bevacizumab

Patients will be treated with erlotinib and bevacizumab. Bevacizumab: 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days) Erlotinib: 150 mg p.o., daily

Drug: Erlotinib
Patients will be treated with erlotinib, 150 mg p.o., daily
Other Names:
  • Tarceva (R) (Roche)

    • Drug: Bevacizumab
    Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days)
    Other Names:
  • Avastin (R) Roche)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Progression Free Survival [From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.]

      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.

    Secondary Outcome Measures

    1. Overall Survival [From the date of enrollment until death, assessed up to 48 months.]

      Time from the date of enrollment until death from any cause.

    2. Time to Treatment Failure [From the date of enrollment until discontinuation of treatment, assessed up to 48 months.]

      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.

    3. Objective Response [Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).]

      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.

    4. Disease Control [Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).]

      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.

    5. Duration of Response [Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).]

      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. 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.

    6. 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 events graded according to NCI CTCAE V4.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Age ≥ 18 years

    • ECOG performance status 0-2

    • Adequate haematological function, coagulation, liver function and renal function

    • Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC)

    • TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radiochemotherapy for stage III disease)

    • Measurable or evaluable disease (according to RECIST 1.1 criteria).

    • Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R)

    Exclusion Criteria:

    • Patients with increased risk of bleeding

    • Patients with clinically significant cardiovascular diseases

    • Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment

    • Patients with gastrointestinal problems

    • Patients with neurologic problems

    • Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma.

    • Patients with any known significant ophthalmologic anomaly of the ocular surface

    • Patients who received prior chemotherapy for metastatic disease

    • Patients who received previous treatment for lung cancer with drugs targeting EGFR or VEGF

    • Pregnancy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Centre Francois Baclesse Caen France 14000
    2 Hôpital de Marseille Marseille France 13915
    3 Hospital Grosshansdorf Grosshansdorf Germany 22927
    4 Thoraxklinik Heidelberg GmbH Heidelberg Germany 69126
    5 Lungenklinik Hemer Hemer Germany 58675
    6 Universitätsklinikum Ulm Ulm Germany 89081
    7 University General Hospital of Heraklion Heraklion Greece
    8 Papageorgias Hospital Thessaloniki Greece
    9 St Vincent's University Hospital Dublin Ireland
    10 St. James's Hospital Dublin Ireland
    11 University Hospital Galway Galway Ireland
    12 Mid-Western Regional Hospital Limerick Ireland
    13 AMCCH Tallaght Ireland
    14 Ospedale San Gerardo Monza Italy 20900
    15 Istituto Oncologico Veneto IRCCS Padova Italy 35128
    16 Casa di Cura Maddalena Palermo Italy 90146
    17 Policlinico Tor Vergata Roma Roma Italy 00133
    18 San Camillo Hospital Roma Italy 00151
    19 Policlinico Umberto Roma Italy 00161
    20 Hospital General Universitario Alicante Alicante Spain 03010
    21 ICO - Hospital Universitari Germans Trias i Pujol Badalona Spain 08916
    22 Hospital De La Santa Creu I Sant Pau Barcelona Spain 08025
    23 Vall d'Hebron University Hospital Barcelona Spain 08035
    24 Hospital Clínic Barcelona Barcelona Spain 08036
    25 ICO - Girona Girona Spain 17007
    26 ICO - Hospital Duran i Reynals L'Hospitalet de Llobregat Spain 08907
    27 Hospital Clinico Universitario San Carlos Madrid Spain 28040
    28 Hospital 12 de Octubre Madrid Spain 28041
    29 Hospital General de Valencia Valencia Spain 46014
    30 Hospital La Fe Valencia Spain 46026
    31 University Hospital Basel Basel Switzerland 4031
    32 Istituto Oncologica della Svizzera Italiana Bellinzona Switzerland 6650
    33 Inselspital Bern Bern Switzerland 3010
    34 Geneva University Hospital Geneva Switzerland 1211
    35 Fondation du centre Pluridisciplinaire d'Oncologie (CePO) Lausanne Switzerland 1011
    36 Kantonsspital Luzern Luzern Switzerland 6016
    37 Kantonsspital St. Gallen St. Gallen Switzerland 9007
    38 Onkologiezentrum Berner Oberland Thun Switzerland 3600
    39 Kantonsspital Winterthur Winterthur Switzerland 8401
    40 University Hospital Zurich Zurich Switzerland 8091
    41 Mid Essex Hospital Services NHS Trust Chelmsford Essex United Kingdom CM1 7ET
    42 Queen's Hospital Burton-upon-Trent United Kingdom DE13 0RB
    43 University Hospitals of Leicester Leicester United Kingdom LE1 5WW
    44 Royal Marsden Hospital London United Kingdom SW3 6JJ
    45 Kent Oncology Centre Maidstone United Kingdom ME16 9QQ
    46 Christie Hospital Manchester Manchester United Kingdom M20 4BX
    47 Wythenshawe Hospital Manchester Manchester United Kingdom M23 9LT
    48 Wrexham Maelor Hospital Wrexham United Kingdom LL13 7TD

    Sponsors and Collaborators

    • ETOP IBCSG Partners Foundation
    • Spanish Lung Cancer Group

    Investigators

    • Study Chair: Rafael Rosell, MD, Catalan Institute of Oncology, Hospital Germans Trias i Pujol
    • Study Chair: Stahel Rolf, MD, Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zuerich
    • Study Chair: Miquel Taron, Medical Oncology Service-ICO, Hospital Germans Trias i Pujol

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    ETOP IBCSG Partners Foundation
    ClinicalTrials.gov Identifier:
    NCT01562028
    Other Study ID Numbers:
    • ETOP 2-11 / MO27911
    • 2011-004481-15
    • MO27911
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Aug 24, 2022
    Last Verified:
    Aug 1, 2022
    Keywords provided by ETOP IBCSG Partners Foundation
    non small cell lung cancer
    advanced
    non-squamous
    EGFR
    mutations
    Additional relevant MeSH terms:
    Lung Neoplasms
    Bevacizumab
    Erlotinib Hydrochloride

    Study Results

    Participant Flow

    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 Detail
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Period Title: Overall Study
    STARTED 37 72
    COMPLETED 34 70
    NOT COMPLETED 3 2

    Baseline Characteristics

    Arm/Group Title T790M Positive T790M Negative Total
    Arm/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). 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). Total of all reporting groups
    Overall Participants 37 72 109
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    69.5
    63
    66.1
    Sex: Female, Male (Count of Participants)
    Female
    25
    67.6%
    42
    58.3%
    67
    61.5%
    Male
    12
    32.4%
    30
    41.7%
    42
    38.5%
    Race and Ethnicity Not Collected (Count of Participants)
    Count of Participants [Participants]
    0
    0%
    Smoking status (Count of Participants)
    Current smoker
    0
    0%
    7
    9.7%
    7
    6.4%
    Former smoker
    10
    27%
    20
    27.8%
    30
    27.5%
    Never smoked
    27
    73%
    45
    62.5%
    72
    66.1%
    Histological diagnosis (Count of Participants)
    Adenocarcinoma
    34
    91.9%
    59
    81.9%
    93
    85.3%
    Adenosquamous carcinoma
    1
    2.7%
    1
    1.4%
    2
    1.8%
    Not otherwise specified
    1
    2.7%
    2
    2.8%
    3
    2.8%
    Unknown
    1
    2.7%
    10
    13.9%
    11
    10.1%
    ECOG performance status (Count of Participants)
    0
    17
    45.9%
    36
    50%
    53
    48.6%
    1
    18
    48.6%
    32
    44.4%
    50
    45.9%
    2
    2
    5.4%
    4
    5.6%
    6
    5.5%
    Brain metastasis (Count of Participants)
    Yes
    7
    18.9%
    14
    19.4%
    21
    19.3%
    No
    30
    81.1%
    58
    80.6%
    88
    80.7%
    Type of EGFR mutation (Count of Participants)
    Deletion of exon 19
    23
    62.2%
    47
    65.3%
    70
    64.2%
    L858R mutation in exon 21
    14
    37.8%
    25
    34.7%
    39
    35.8%
    BRCA1 mRNA expression (Count of Participants)
    Low (<9.2)
    10
    27%
    13
    18.1%
    23
    21.1%
    High (≥9.2)
    10
    27%
    13
    18.1%
    23
    21.1%
    No material or no value
    17
    45.9%
    46
    63.9%
    63
    57.8%
    AEG1 mRNA expression (Count of Participants)
    Low (<1)
    11
    29.7%
    20
    27.8%
    31
    28.4%
    High (≥1)
    12
    32.4%
    18
    25%
    30
    27.5%
    No material or no value
    14
    37.8%
    34
    47.2%
    48
    44%

    Outcome Measures

    1. Primary Outcome
    Title Progression Free Survival
    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.
    Time Frame From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Median (95% Confidence Interval) [months]
    16
    10.5
    2. Secondary Outcome
    Title Overall Survival
    Description Time from the date of enrollment until death from any cause.
    Time Frame From the date of enrollment until death, assessed up to 48 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Median (95% Confidence Interval) [months]
    NA
    28.2
    3. Secondary Outcome
    Title Time to Treatment Failure
    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.
    Time Frame From the date of enrollment until discontinuation of treatment, assessed up to 48 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Median (95% Confidence Interval) [months]
    13.4
    8.3
    4. Secondary Outcome
    Title Objective Response
    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.
    Time Frame Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

    Outcome Measure Data

    Analysis Population Description
    Patients with only 1 tumor assessment are classified as "Non-Evaluable", because they cannot be accounted for the Objective Response rate.
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Complete Response
    3
    8.1%
    3
    4.2%
    Partial Response
    24
    64.9%
    54
    75%
    Stable Disease
    8
    21.6%
    9
    12.5%
    Progressive Disease
    1
    2.7%
    3
    4.2%
    Non-Evaluable
    1
    2.7%
    3
    4.2%
    5. Secondary Outcome
    Title Disease Control
    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.
    Time Frame Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Disease Control
    35
    94.6%
    66
    91.7%
    No Disease Control
    2
    5.4%
    6
    8.3%
    6. Secondary Outcome
    Title Duration of Response
    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. 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.
    Time Frame Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 37 72
    Median (95% Confidence Interval) [months]
    NA
    12
    7. Secondary Outcome
    Title Adverse Events
    Description Adverse events graded according to NCI CTCAE V4.
    Time Frame Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

    Outcome Measure Data

    Analysis Population Description
    Three patients never started treatment (2 lost to follow-up, one from each arm and 1 withdrawal from T790M negative arm).
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    Measure Participants 36 70
    Experienced AE/SAE
    36
    97.3%
    69
    95.8%
    No AE/SAE
    0
    0%
    1
    1.4%
    Experienced SAE
    12
    32.4%
    19
    26.4%

    Adverse Events

    Time Frame 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 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).
    Arm/Group Title T790M Positive T790M Negative
    Arm/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). 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).
    All Cause Mortality
    T790M Positive T790M Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/36 (2.8%) 0/70 (0%)
    Serious Adverse Events
    T790M Positive T790M Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/36 (33.3%) 19/70 (27.1%)
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation 0/36 (0%) 1/70 (1.4%)
    Cardiac disorders
    Acute coronary syndrome 0/36 (0%) 1/70 (1.4%)
    Gastrointestinal disorders
    Abdominal pain 1/36 (2.8%) 1/70 (1.4%)
    Colonic perforation 1/36 (2.8%) 1/70 (1.4%)
    Diarrhea 0/36 (0%) 2/70 (2.9%)
    Pancreatitis 0/36 (0%) 2/70 (2.9%)
    Anal hemorrhage 1/36 (2.8%) 0/70 (0%)
    Colitis 1/36 (2.8%) 0/70 (0%)
    Dysphagia 1/36 (2.8%) 0/70 (0%)
    Other 0/36 (0%) 1/70 (1.4%)
    Vomiting 1/36 (2.8%) 0/70 (0%)
    General disorders
    Fever 0/36 (0%) 1/70 (1.4%)
    Hepatobiliary disorders
    Other 0/36 (0%) 1/70 (1.4%)
    Infections and infestations
    Appendicitis 0/36 (0%) 2/70 (2.9%)
    Lung infection 0/36 (0%) 2/70 (2.9%)
    Urinary tract infection 2/36 (5.6%) 0/70 (0%)
    Abdominal infection 1/36 (2.8%) 0/70 (0%)
    Biliary tract infection 0/36 (0%) 1/70 (1.4%)
    Bone infection 0/36 (0%) 1/70 (1.4%)
    Bronchial infection 1/36 (2.8%) 0/70 (0%)
    Sepsis 1/36 (2.8%) 1/70 (1.4%)
    Injury, poisoning and procedural complications
    Hip fracture 1/36 (2.8%) 0/70 (0%)
    Investigations
    Serum amylase increased 1/36 (2.8%) 0/70 (0%)
    Metabolism and nutrition disorders
    Dehydration 2/36 (5.6%) 0/70 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/36 (0%) 1/70 (1.4%)
    Other 0/36 (0%) 1/70 (1.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other 0/36 (0%) 1/70 (1.4%)
    Nervous system disorders
    Other 0/36 (0%) 2/70 (2.9%)
    Cognitive disturbance 1/36 (2.8%) 0/70 (0%)
    Dizziness 0/36 (0%) 1/70 (1.4%)
    Seizure 0/36 (0%) 1/70 (1.4%)
    Psychiatric disorders
    Confusion 2/36 (5.6%) 0/70 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax 0/36 (0%) 1/70 (1.4%)
    Other 0/36 (0%) 1/70 (1.4%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 1/36 (2.8%) 0/70 (0%)
    Vascular disorders
    Thromboembolic event 1/36 (2.8%) 3/70 (4.3%)
    Hypotension 1/36 (2.8%) 0/70 (0%)
    Other (Not Including Serious) Adverse Events
    T790M Positive T790M Negative
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 36/36 (100%) 69/70 (98.6%)
    Blood and lymphatic system disorders
    Anemia 1/36 (2.8%) 4/70 (5.7%)
    Other 2/36 (5.6%) 2/70 (2.9%)
    Cardiac disorders
    Chest pain - cardiac 0/36 (0%) 3/70 (4.3%)
    Ear and labyrinth disorders
    Vertigo 0/36 (0%) 4/70 (5.7%)
    Eye disorders
    Conjunctivitis 9/36 (25%) 9/70 (12.9%)
    Other 5/36 (13.9%) 7/70 (10%)
    Dry eye 3/36 (8.3%) 5/70 (7.1%)
    Watering eyes 2/36 (5.6%) 1/70 (1.4%)
    Gastrointestinal disorders
    Diarrhea 30/36 (83.3%) 55/70 (78.6%)
    Nausea 13/36 (36.1%) 20/70 (28.6%)
    Mucositis oral 15/36 (41.7%) 15/70 (21.4%)
    Abdominal pain 4/36 (11.1%) 15/70 (21.4%)
    Constipation 8/36 (22.2%) 12/70 (17.1%)
    Vomiting 7/36 (19.4%) 1/70 (1.4%)
    Other 6/36 (16.7%) 3/70 (4.3%)
    Hemorrhoids 4/36 (11.1%) 5/70 (7.1%)
    Anal hemorrhage 4/36 (11.1%) 3/70 (4.3%)
    Dry mouth 5/36 (13.9%) 3/70 (4.3%)
    Oral hemorrhage 3/36 (8.3%) 5/70 (7.1%)
    Dysphagia 4/36 (11.1%) 2/70 (2.9%)
    Gastroesophageal reflux disease 2/36 (5.6%) 5/70 (7.1%)
    Dyspepsia 1/36 (2.8%) 3/70 (4.3%)
    Gastritis 2/36 (5.6%) 2/70 (2.9%)
    Hemorrhoidal hemorrhage 2/36 (5.6%) 2/70 (2.9%)
    Oral pain 2/36 (5.6%) 1/70 (1.4%)
    General disorders
    Fatigue 23/36 (63.9%) 34/70 (48.6%)
    Pain 10/36 (27.8%) 12/70 (17.1%)
    Edema limbs 5/36 (13.9%) 4/70 (5.7%)
    Fever 3/36 (8.3%) 5/70 (7.1%)
    Flu like symptoms 3/36 (8.3%) 4/70 (5.7%)
    Other 3/36 (8.3%) 3/70 (4.3%)
    Non-cardiac chest pain 2/36 (5.6%) 2/70 (2.9%)
    Infections and infestations
    Paronychia 8/36 (22.2%) 8/70 (11.4%)
    Urinary tract infection 6/36 (16.7%) 7/70 (10%)
    Upper respiratory infection 6/36 (16.7%) 6/70 (8.6%)
    Other 5/36 (13.9%) 5/70 (7.1%)
    Nail infection 3/36 (8.3%) 6/70 (8.6%)
    Lung infection 2/36 (5.6%) 2/70 (2.9%)
    Mucosal infection 3/36 (8.3%) 3/70 (4.3%)
    Bronchial infection 2/36 (5.6%) 2/70 (2.9%)
    Rhinitis infective 1/36 (2.8%) 3/70 (4.3%)
    Lip infection 0/36 (0%) 3/70 (4.3%)
    Investigations
    Alanine aminotransferase increase 8/36 (22.2%) 21/70 (30%)
    Aspartate aminotransferase increase 7/36 (19.4%) 21/70 (30%)
    Creatinine increased 3/36 (8.3%) 2/70 (2.9%)
    Blood bilirubin increased 1/36 (2.8%) 3/70 (4.3%)
    Metabolism and nutrition disorders
    Anorexia 10/36 (27.8%) 18/70 (25.7%)
    Other 4/36 (11.1%) 7/70 (10%)
    Musculoskeletal and connective tissue disorders
    Bone pain 8/36 (22.2%) 13/70 (18.6%)
    Back pain 4/36 (11.1%) 15/70 (21.4%)
    Arthralgia 7/36 (19.4%) 7/70 (10%)
    Pain in extremity 6/36 (16.7%) 8/70 (11.4%)
    Myalgia 2/36 (5.6%) 6/70 (8.6%)
    Other 1/36 (2.8%) 4/70 (5.7%)
    Chest wall pain 1/36 (2.8%) 4/70 (5.7%)
    Arthritis 2/36 (5.6%) 2/70 (2.9%)
    Nervous system disorders
    Headache 8/36 (22.2%) 13/70 (18.6%)
    Dysgeusia 6/36 (16.7%) 12/70 (17.1%)
    Dizziness 6/36 (16.7%) 10/70 (14.3%)
    Paresthesia 3/36 (8.3%) 6/70 (8.6%)
    Other 2/36 (5.6%) 2/70 (2.9%)
    Aphonia 4/36 (11.1%) 0/70 (0%)
    Peripheral sensory neuropathy 1/36 (2.8%) 3/70 (4.3%)
    Psychiatric disorders
    Depression 2/36 (5.6%) 7/70 (10%)
    Anxiety 2/36 (5.6%) 3/70 (4.3%)
    Insomnia 2/36 (5.6%) 2/70 (2.9%)
    Renal and urinary disorders
    Proteinuria 27/36 (75%) 34/70 (48.6%)
    Hematuria 1/36 (2.8%) 4/70 (5.7%)
    Other 0/36 (0%) 5/70 (7.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough 24/36 (66.7%) 30/70 (42.9%)
    Epistaxis 18/36 (50%) 20/70 (28.6%)
    Dyspnea 12/36 (33.3%) 18/70 (25.7%)
    Other 4/36 (11.1%) 4/70 (5.7%)
    Voice alteration 5/36 (13.9%) 4/70 (5.7%)
    Hoarseness 3/36 (8.3%) 5/70 (7.1%)
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 28/36 (77.8%) 55/70 (78.6%)
    Dry skin 17/36 (47.2%) 20/70 (28.6%)
    Rash acneiform 10/36 (27.8%) 13/70 (18.6%)
    Other 9/36 (25%) 13/70 (18.6%)
    Alopecia 8/36 (22.2%) 11/70 (15.7%)
    Pruritus 10/36 (27.8%) 6/70 (8.6%)
    Erythema multiforme 6/36 (16.7%) 6/70 (8.6%)
    Nail ridging 2/36 (5.6%) 3/70 (4.3%)
    Nail discoloration 2/36 (5.6%) 1/70 (1.4%)
    Palmar-plantar erythrodysesthesia syndrome 0/36 (0%) 3/70 (4.3%)
    Skin ulceration 0/36 (0%) 3/70 (4.3%)
    Vascular disorders
    Hypertension 33/36 (91.7%) 62/70 (88.6%)
    Thromboembolic event 2/36 (5.6%) 2/70 (2.9%)
    Hematoma 2/36 (5.6%) 3/70 (4.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Heidi Roschitzki-Voser
    Organization European Thoracic Oncology Platform (ETOP)
    Phone +41 31 511 94 18
    Email belief@etop-eu.org
    Responsible Party:
    ETOP IBCSG Partners Foundation
    ClinicalTrials.gov Identifier:
    NCT01562028
    Other Study ID Numbers:
    • ETOP 2-11 / MO27911
    • 2011-004481-15
    • MO27911
    First Posted:
    Mar 23, 2012
    Last Update Posted:
    Aug 24, 2022
    Last Verified:
    Aug 1, 2022