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
Mené auprès de 64 patientes japonaises atteintes d'un carcinome métastatique du rein réfractaire aux cytokines, cet essai de phase II évalue l'efficacité et la tolérabilité de l'axinitib, un inhibiteur des récepteurs VEGFR-1, 2 et 3
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 5 mg 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 [greater-or-equal, slanted]3), hand-foot syndrome (75%; 22% grade [greater-or-equal, slanted]3) and diarrhoea (64%; 5% grade [greater-or-equal, slanted]3). Eighteen patients (28%) developed proteinuria [greater-or-equal, slanted]2 g/24 h 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 [greater-or-equal, slanted]2 g/24 h (hazard ratio [HR] = 5.457, P = 0.0035 in patients with baseline proteinuria [greater-or-equal, slanted]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.