title: Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial.
abstract: OBJECTIVE
  To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC).
  
  
  METHODS
  In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS).
  
  
  RESULTS
  Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) -15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2.
  
  
  CONCLUSIONS
  Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.
authors.affiliation: Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain; Jill Clancy, Kongming Wang, Andreas G. Niethammer, Subramanian Hariharan, Pfizer, New York, NY; and Bernard Escudier, Institut Gustave Roussy, Villejuif, France.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.forename: Jill
authors.initials: J
authors.lastname: Clancy
authors.forename: Kongming
authors.initials: K
authors.lastname: Wang
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Niethammer
authors.forename: Subramanian
authors.initials: S
authors.lastname: Hariharan
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D016016:Proportional Hazards Models; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016898:Interferon-alpha; D000068258:Bevacizumab; C401859:temsirolimus; D020123:Sirolimus