title: Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted.
  
  
  METHODS
  In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-line therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. This trial is registered with centerwatch.com, number BO17705E.
  
  
  RESULTS
  325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10.2 months vs 5.4 months; HR 0.63, 95% CI 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]).
  
  
  CONCLUSIONS
  The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.
authors.affiliation: Department of Medicine, Institut Gustave Roussy, Villejuif, France. escudier@igr.fr
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Anna
authors.initials: A
authors.lastname: Pluzanska
authors.forename: Piotr
authors.initials: P
authors.lastname: Koralewski
authors.forename: Alain
authors.initials: A
authors.lastname: Ravaud
authors.forename: Sergio
authors.initials: S
authors.lastname: Bracarda
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Marek
authors.initials: M
authors.lastname: Filipek
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.forename: Emilio
authors.initials: E
authors.lastname: Bajetta
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Bay
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodrogi
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Jagiello-Gruszfeld
authors.forename: Nicola
authors.initials: N
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab