title: Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma.
abstract: OBJECTIVE
  To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response.
  
  
  METHODS
  Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured.
  
  
  RESULTS
  Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome.
  
  
  CONCLUSIONS
  Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting.
authors.affiliation: Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Avenue, Desk R35, Cleveland, OH 44195, USA. rinib2@ccf.org
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Kim
authors.initials: K
authors.lastname: Margolin
authors.forename: Charles S
authors.initials: CS
authors.lastname: Harmon
authors.forename: Samuel E
authors.initials: SE
authors.lastname: DePrimo
authors.forename: Sindy T
authors.initials: ST
authors.lastname: Kim
authors.forename: Isan
authors.initials: I
authors.lastname: Chen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: George
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D013997:Time Factors; D017211:Treatment Failure; D014481:United States; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D042582:Vascular Endothelial Growth Factor C / Q000097:blood; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D007211:Indoles; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D011758:Pyrroles; C467484:VEGFA protein, human; C467486:VEGFC protein, human; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D000072483:Placenta Growth Factor; D000068258:Bevacizumab; D040321:Vascular Endothelial Growth Factor Receptor-3; D000077210:Sunitinib