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Medline ® Abstract for Reference 10

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

10
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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.
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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
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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.
AD
Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
PMID