title: Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial.
abstract: BACKGROUND
  Combining targeted treatments for renal cell carcinoma has been suggested as a possible method to improve treatment efficacy. We aimed to assess the potential synergistic or additive effect of the combination of bevacizumab, directed against the VEGF receptor, and temsirolimus, an mTOR inhibitor, in metastatic renal cell carcinoma.
  
  
  METHODS
  TORAVA was an open-label, multicentre randomised phase 2 study undertaken in 24 centres in France. Patients aged 18 years or older who had untreated metastatic renal cell carcinoma were randomly assigned (2:1:1) to receive the combination of bevacizumab (10 mg/kg every 2 weeks) and temsirolimus (25 mg weekly; group A), or one of the standard treatments: sunitinib (50 mg/day for 4 weeks followed by 2 weeks off; group B), or the combination of interferon alfa (9 mIU three times per week) and bevacizumab (10 mg/kg every 2 weeks; group C). Randomisation was done centrally and independently from other study procedures with computer-generated permuted blocks of four and eight patients stratified by participating centre and Eastern Cooperative Oncology Group performance status. The primary endpoint was progression-free survival (PFS) at 48 weeks (four follow-up CT scans), which was expected to be above 50% in group A. Analysis was by intention to treat. The study is ongoing for long-term overall survival. This study is registered with ClinicalTrials.gov, number NCT00619268.
  
  
  RESULTS
  Between March 3, 2008 and May 6, 2009, 171 patients were randomly assigned: 88 to the experimental group (group A), 42 to group B, and 41 to group C. PFS at 48 weeks was 29.5% (26 of 88 patients, 95% CI 20.0-39.1) in group A, 35.7% (15 of 42, 21.2-50.2) in group B, and 61.0% (25 of 41, 46.0-75.9) in group C. Median PFS was 8.2 months (95% CI 7.0-9.6) in group A, 8.2 months (5.5-11.7) in group B, and 16.8 months (6.0-26.0) in group C. 45 (51%) of 88 patients in group A stopped treatment for reasons other than progression compared with five (12%) of 42 in group B and 15 (38%) of 40 in group C. Grade 3 or worse adverse events were reported in 68 (77%) of 88 patients in group A versus 25 (60%) of 42 in group B and 28 (70%) of 40 in group C. Serious adverse events were reported in 39 (44%) of 88, 13 (31%) of 42, and 18 (45%) of 40 patients in groups A, B, and C, respectively.
  
  
  CONCLUSIONS
  The toxicity of the temsirolimus and bevacizumab combination was much higher than anticipated and limited treatment continuation over time. Clinical activity was low compared with the benefit expected from sequential use of each targeted therapy. This combination cannot be recommended for first-line treatment in patients with metastatic renal cell carcinoma.
  
  
  BACKGROUND
  French Ministry of Health and Wyeth Pharmaceuticals.
authors.affiliation: Medical Oncology Department, University of Lyon, Centre Léon Bérard, Lyon, France. negrier@lyon.fnclcc.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Négrier
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Gravis
authors.forename: David
authors.initials: D
authors.lastname: Pérol
authors.forename: Christine
authors.initials: C
authors.lastname: Chevreau
authors.forename: Rémy
authors.initials: R
authors.lastname: Delva
authors.forename: Jacques-Olivier
authors.initials: JO
authors.lastname: Bay
authors.forename: Ellen
authors.initials: E
authors.lastname: Blanc
authors.forename: Céline
authors.initials: C
authors.lastname: Ferlay
authors.forename: Lionnel
authors.initials: L
authors.lastname: Geoffrois
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rolland
authors.forename: Eric
authors.initials: E
authors.lastname: Legouffe
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sevin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laguerre
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011758:Pyrroles / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007211:Indoles; D016898:Interferon-alpha; D011758:Pyrroles; D000068258:Bevacizumab; C401859:temsirolimus; D000077210:Sunitinib; D020123:Sirolimus