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

Eur J Cancer. 2011 Nov;47(17):2592-602. doi: 10.1016/j.ejca.2011.07.014. Epub 2011 Aug 31.


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).

Patients and 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.

Trial registration: NCT00569946.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / adverse effects*
  • Angiogenesis Inhibitors / therapeutic use
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / therapeutic use
  • Axitinib
  • Biomarkers, Tumor / blood
  • Carcinoma, Renal Cell / blood
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / secondary
  • Disease-Free Survival
  • Female
  • Humans
  • Imidazoles / adverse effects*
  • Imidazoles / therapeutic use
  • Indazoles / adverse effects*
  • Indazoles / therapeutic use
  • Kidney Neoplasms / blood
  • Kidney Neoplasms / drug therapy*
  • Male
  • Middle Aged
  • Prognosis
  • Proteinuria / chemically induced*
  • Proteinuria / diagnosis
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-2 / blood


  • Angiogenesis Inhibitors
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Imidazoles
  • Indazoles
  • Axitinib
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-2

Associated data