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669�C0.999; P?=?0.049).[57] On the basis of these data, sunitinib has emerged as a front-line agent for mRCC.[58] The safety and efficacy of the sunitinib therapy were confirmed in an expanded-access trial. Discontinuation of treatment because of adverse events occurred in 8% of the patients, and clinical benefit (objective response or stable disease for at least 3 months) was achieved in 76%.[59] In this trial, sunitinib was also found to be active against non-clear cell RCC, and the median PFS of this subgroup was 7.8 months. Sunitinib was also found to be active in the subgroups of patients with brain metastasis (n?=?320; median PFS: 5.6 months), poor performance status (Eastern Cooperative Oncology Group Performance Status ��2; n?=?582; median PFS: 5.1 month), and an age ��65 years (n?=?1442; median PFS: 11.3 months).[59] Escudier et?al. investigated http://www.selleckchem.com/products/bay-57-1293.html the efficacy and tolerability of continuous sunitinib therapy (37.5?mg per day for 6 weeks) in patients with cytokine-refractory metastatic RCC, and found similar results to those achieved with an intermittent administration schedule (50?mg per day for 4 weeks and 2 weeks off).[60] Barrios et?al. reported similar results in the first-line setting.[61] In a Japanese phase?II trial of treatment-naive patients and cytokine-refractory patients, the median PFS http://www.selleck.cn/products/CAL-101.html was 12.2 and 10.6 months for first-line and pretreated patients, respectively. A total of 14 patients died in each group (56% and 54%), and the median OS was 33.1 and 32.5 months, respectively.[62] Although the number of subjects was small, the results of this study suggested that sunitinib can also be considered as second-line therapy after the failure of cytokines in Japanese patients with mRCC. Pazopanib is an oral multi-targeted TKI of VEGFR-1, ?2 and ?3, PDGFR-��, -��, http://www.selleckchem.com/products/gsk2126458.html and cKIT.[63] A randomized, double-blind, placebo-controlled phase?III study was carried out in 435 patients, of whom 233 were treatment naive (54%) and 202 had received cytokine therapy (46%). PFS was significantly prolonged by pazopanib compared with placebo in the overall study population (median PFS was 9.2 vs 4.2 months; HR 0.46; 95% CI 0.34�C0.62; P?=?0.0001), as well as in the treatment-naive population (median PFS was 11.1 vs 2.8 months; HR 0.40; 95% CI 0.27�C0.60; P?=?0.0001) and the cytokine-treated population (median PFS was 7.4 vs 4.2 months; HR 0.54; 95% CI 0.35�C0.84; P?=?0.001).[64] Based on these results, guidelines recommend pazopanib for both first-line therapy and as a second-line agent after cytokine therapy. Grade?3 hepatotoxicity might be more common with pazopanib.[33] Powles et?al. reported there was no significant difference in the overall number of toxic events (grade?1�C4) as a result of sunitinib and pazopanib (the mean number of events per patient was 1.97 vs 1.96, P?>?0.05). There were more grade?2�C4 events with sunitinib therapy (HR 1.67; 95% CI 1.11�C2.56; P?