title: Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma.
abstract: BACKGROUND
  Axitinib (AG-013736) is an oral, selective and potent inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3. This phase II study investigated axitinib efficacy, safety and biomarkers in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (mRCC).
  
  
  METHODS
  In an open-label, multicentre study, 64 patients received an axitinib starting dose of 5mg twice daily.
  
  
  RESULTS
  Objective response rate (ORR) was 50.0% and median progression-free survival (PFS) was 11.0 months per independent review committee. Common treatment-related adverse events were hypertension (84%; 70% grade ≥3), hand-foot syndrome (75%; 22% grade ≥3) and diarrhoea (64%; 5% grade ≥3). Eighteen patients (28%) developed proteinuria ≥2g/24h and required dose reduction or treatment interruption/discontinuation. Proteinuria was a major cause for treatment discontinuation. Baseline urine protein levels were associated with development of proteinuria ≥2g/24h (hazard ratio [HR]=5.457, P=0.0035 in patients with baseline proteinuria ≥1+ versus <1+). Baseline urine protein levels correlated more strongly with axitinib-related proteinuria than other baseline renal function test values or blood pressure. Patients with greater decreases in soluble VEGFR-2 concentrations had significantly higher ORR and longer PFS than those with smaller decreases (ORR: 64.5% versus 37.5%, P=0.045; median PFS: 12.9 months versus 9.2 months, HR=0.42, P=0.01).
  
  
  CONCLUSIONS
  Axitinib showed significant antitumour activity and was well tolerated in Japanese mRCC patients. Baseline proteinuria and soluble VEGFR-2 levels may be key indicators of axitinib-induced proteinuria and efficacy, respectively.
authors: Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors: Yoshihiko
authors: Y
authors: Tomita
authors: Hirotsugu
authors: H
authors: Uemura
authors: Hiroyuki
authors: H
authors: Fujimoto
authors: Hiro-omi
authors: HO
authors: Kanayama
authors: Nobuo
authors: N
authors: Shinohara
authors: Hayakazu
authors: H
authors: Nakazawa
authors: Keiji
authors: K
authors: Imai
authors: Yoshiko
authors: Y
authors: Umeyama
authors: Seiichiro
authors: S
authors: Ozono
authors: Seiji
authors: S
authors: Naito
authors: Hideyuki
authors: H
authors: Akaza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000077784:Axitinib; D014408:Biomarkers, Tumor / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D007191:Indazoles / Q000009:adverse effects* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011507:Proteinuria / Q000139:chemically induced* / Q000175:diagnosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2