BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC) (BELIEF)

An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

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.

Study Overview

• Status: Completed
• Conditions: Lung Cancer
• Intervention / Treatment: Drug: Erlotinib; Drug: Bevacizumab

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 Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Caen, France, 14000
    • Centre François Baclesse
  • Marseille, France, 13915
    • Hôpital de Marseille
• Germany
  • Grosshansdorf, Germany, 22927
    • Hospital Grosshansdorf
  • Heidelberg, Germany, 69126
    • Thoraxklinik Heidelberg GmbH
  • Hemer, Germany, 58675
    • Lungenklinik Hemer
  • Ulm, Germany, 89081
    • Universitätsklinikum Ulm
• Greece
  • Heraklion, Greece
    • University General Hospital of Heraklion
  • Thessaloniki, Greece
    • Papageorgias Hospital
• Ireland
  • Dublin, Ireland
    • St Vincent's University Hospital
  • Dublin, Ireland
    • St. James's Hospital
  • Galway, Ireland
    • University Hospital Galway
  • Limerick, Ireland
    • Mid-Western Regional Hospital
  • Tallaght, Ireland
    • AMCCH
• Italy
  • Monza, Italy, 20900
    • Ospedale San Gerardo
  • Padova, Italy, 35128
    • Istituto Oncologico Veneto IRCCS
  • Palermo, Italy, 90146
    • Casa di Cura Maddalena
  • Roma, Italy, 00133
    • Policlinico Tor Vergata Roma
  • Roma, Italy, 00151
    • San Camillo Hospital
  • Roma, Italy, 00161
    • Policlinico Umberto
• Spain
  • Alicante, Spain, 03010
    • Hospital General Universitario Alicante
  • Badalona, Spain, 08916
    • ICO - Hospital Universitari Germans Trias i Pujol
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08036
    • Hospital Clinic Barcelona
  • Barcelona, Spain, 08035
    • Vall D'Hebron University Hospital
  • Girona, Spain, 17007
    • ICO - Girona
  • L'Hospitalet de Llobregat, Spain, 08907
    • ICO - Hospital Duran i Reynals
  • Madrid, Spain, 28041
    • Hospital 12 de octubre
  • Madrid, Spain, 28040
    • Hospital Clínico Universitario San Carlos
  • Valencia, Spain, 46026
    • Hospital la Fe
  • Valencia, Spain, 46014
    • Hospital General de Valencia
• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel
  • Bellinzona, Switzerland, 6650
    • Istituto Oncologica della Svizzera Italiana
  • Bern, Switzerland, 3010
    • Inselspital Bern
  • Geneva, Switzerland, 1211
    • Geneva University Hospital
  • Lausanne, Switzerland, 1011
    • Fondation du centre Pluridisciplinaire d'Oncologie (CePO)
  • Luzern, Switzerland, 6016
    • Kantonsspital Luzern
  • St. Gallen, Switzerland, 9007
    • Kantonsspital St. Gallen
  • Thun, Switzerland, 3600
    • Onkologiezentrum Berner Oberland
  • Winterthur, Switzerland, 8401
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8091
    • University Hospital Zurich
• United Kingdom
  • Burton-upon-Trent, United Kingdom, DE13 0RB
    • Queen's Hospital
  • Leicester, United Kingdom, LE1 5WW
    • University Hospitals of Leicester
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hospital
  • Maidstone, United Kingdom, ME16 9QQ
    • Kent Oncology Centre
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital Manchester
  • Manchester, United Kingdom, M23 9LT
    • Wythenshawe Hospital Manchester
  • Wrexham, United Kingdom, LL13 7TD
    • Wrexham Maelor Hospital
  • Essex
    • Chelmsford, Essex, United Kingdom, CM1 7ET
      • Mid Essex Hospital Services NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Time from the date of enrollment until death from any cause.	From the date of enrollment until death, assessed up to 48 months.
Time to Treatment Failure	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.	From the date of enrollment until discontinuation of treatment, assessed up to 48 months.
Objective Response	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.	Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
Disease Control	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.	Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
Duration of Response	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.	Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).
Adverse Events	Adverse events graded according to NCI CTCAE V4.	Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

Collaborators and Investigators

• Sponsor: ETOP IBCSG Partners Foundation
• Collaborators: 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

Publications and helpful links

General Publications

• Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004 Jun 4;304(5676):1497-500. doi: 10.1126/science.1099314. Epub 2004 Apr 29.
• Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, Terrasa J, Munoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L; Spanish Lung Cancer Group in collaboration with Groupe Francais de Pneumo-Cancerologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012 Mar;13(3):239-46. doi: 10.1016/S1470-2045(11)70393-X. Epub 2012 Jan 26.
• Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, Johnson BE, Eck MJ, Tenen DG, Halmos B. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005 Feb 24;352(8):786-92. doi: 10.1056/NEJMoa044238.
• Kabbinavar F, Miller VA, Johnson BE, O'Connor P, Soh C-H, ATLAS Investigators. Overall survival in ATLAS, a Phase IIIb trial comparing bevacizumab therapy +/- erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2010; 28 (May suppl; abstr 7526).
• Rosell R, Dafni U, Felip E, Curioni-Fontecedro A, Gautschi O, Peters S, Massuti B, Palmero R, Aix SP, Carcereny E, Fruh M, Pless M, Popat S, Kotsakis A, Cuffe S, Bidoli P, Favaretto A, Froesch P, Reguart N, Puente J, Coate L, Barlesi F, Rauch D, Thomas M, Camps C, Gomez-Codina J, Majem M, Porta R, Shah R, Hanrahan E, Kammler R, Ruepp B, Rabaglio M, Kassapian M, Karachaliou N, Tam R, Shames DS, Molina-Vila MA, Stahel RA; BELIEF collaborative group. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial. Lancet Respir Med. 2017 May;5(5):435-444. doi: 10.1016/S2213-2600(17)30129-7. Epub 2017 Apr 10. Erratum In: Lancet Respir Med. 2018 Dec;6(12):e57.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): October 31, 2018
• Study Completion (Actual): October 31, 2018

Study Registration Dates

• First Submitted: March 22, 2012
• First Submitted That Met QC Criteria: March 22, 2012
• First Posted (Estimate): March 23, 2012

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 23, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: EGFR; advanced; mutations; non small cell lung cancer; non-squamous
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Bevacizumab
• Other Study ID Numbers: ETOP 2-11 / MO27911; 2011-004481-15 (EudraCT Number); MO27911 (Other Identifier: Roche)