• Yoshihiko Tomita, Hirotsugu Uemura, Hiroyuki Fujimoto, Hiro-omi Kanayama, Nobuo Shinohara, Hayakazu Nakazawa, Keiji Imai, Yoshiko Umeyama, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza, and Japan Axitinib Phase II Study Group.
• Department of Urology, Yamagata University Faculty of Medicine, Yamagata, Japan.
• Eur. J. Cancer. 2011 Nov 1; 47 (17): 2592-602.

BackgroundAxitinib (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 MethodsIn an open-label, multicentre study, 64 patients received an axitinib starting dose of 5mg twice daily.ResultsObjective 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).ConclusionsAxitinib 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.Copyright © 2011 Elsevier Ltd. All rights reserved.

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