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Medline ® Abstract for Reference 10

of 'Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects'

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.
Tomita Y, Uemura H, Fujimoto H, Kanayama HO, Shinohara N, Nakazawa H, Imai K, Umeyama Y, Ozono S, Naito S, Akaza H, Japan Axitinib Phase II Study Group
Eur J Cancer. 2011 Nov;47(17):2592-602. 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.
Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.