title: BEST: A Randomized Phase II Study of Vascular Endothelial Growth Factor, RAF Kinase, and Mammalian Target of Rapamycin Combination Targeted Therapy With Bevacizumab, Sorafenib, and Temsirolimus in Advanced Renal Cell Carcinoma--A Trial of the ECOG-ACRIN Cancer Research Group (E2804).
abstract: OBJECTIVE
  On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade.
  
  
  METHODS
  A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point.
  
  
  RESULTS
  Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms.
  
  
  CONCLUSIONS
  The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy.
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ. kflaherty@partners.org.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Judith B
authors.initials: JB
authors.lastname: Manola
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Janice J
authors.initials: JJ
authors.lastname: Dutcher
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Margolin
authors.affiliation: Keith T. Flaherty, University of Pennsylvania, Philadelphia, PA; Judith B. Manola, Dana-Farber Cancer Institute; David F. McDermott and Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Michael Pins, Advocate Lutheran General Hospital, Park Ridge, IL; Janice J. Dutcher, Montefiore Medical Center, Bronx, NY; Daniel J. George, Duke University Medical Center, Durham, NC; Kim A. Margolin, Seattle Cancer Care Alliance, University of Washington, Seattle, WA; and Robert S. DiPaola, Cancer Institute of New Jersey at Hamilton, New Brunswick, NJ.
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; C401859:temsirolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048490:raf Kinases; D020123:Sirolimus