title: Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer.
  
  
  METHODS
  This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824.
  
  
  RESULTS
  Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]).
  
  
  CONCLUSIONS
  Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy.
  
  
  BACKGROUND
  GERCOR and F Hoffmann-La Roche.
authors.affiliation: Hôpital Henri Mondor, Assistance Publique - Hôpitaux de Paris, Paris-Est Créteil University, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tournigand
authors.affiliation: Institut Hospitalier Franco-Britannique, Levallois-Perret, France.
authors.forename: Benoist
authors.initials: B
authors.lastname: Chibaudel
authors.affiliation: Hôpital Charles Lemoyne, Greenfield Park, QC, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Samson
authors.affiliation: Universitätsklinik für Innere Medizin I, Wien, Austria.
authors.forename: Werner
authors.initials: W
authors.lastname: Scheithauer
authors.affiliation: Methodology and Quality of Life Unit, University Hospital of Besançon, Besançon, France.
authors.forename: Dewi
authors.initials: D
authors.lastname: Vernerey
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Mésange
authors.affiliation: Hôpital Privé Jean Mermoz, Lyon, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Lledo
authors.affiliation: Institut Paoli Calmettes, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Viret
authors.affiliation: Centre Catherine de Sienne, Nantes, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Ramée
authors.affiliation: Centre Hospitalier Universitaire Dupuytren, Limoges, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Tubiana-Mathieu
authors.affiliation: Centre Hospitalier Layné, Mont-de-Marsan, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dauba
authors.affiliation: Clinique Victor Hugo, Le Mans, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dupuis
authors.affiliation: Hôpital Ambroise Paré, Marseille Cedex, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Rinaldi
authors.affiliation: Hôpital Foch, Suresnes, France.
authors.forename: May
authors.initials: M
authors.lastname: Mabro
authors.affiliation: Cité de la Santé de Laval, Laval, QC, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Aucoin
authors.affiliation: Hôpital Charles Lemoyne, Greenfield Park, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Latreille
authors.affiliation: Methodology and Quality of Life Unit, University Hospital of Besançon, Besançon, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Bonnetain
authors.affiliation: Institut Mutualiste Montsouris, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louvet
authors.affiliation: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
authors.affiliation: Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: André
authors.affiliation: Institut Hospitalier Franco-Britannique, Levallois-Perret, France. Electronic address: aimerydegramont@gmail.com.
authors.forename: Aimery
authors.initials: A
authors.lastname: de Gramont
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride