A B S T R A C T PurposeA randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-␣) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported. Patients and MethodsSeven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-␣ 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up. ResultsMedian overall survival was greater in the sunitinib group than in the IFN-␣ group (26.4 v 21.8 months, respectively; hazard ratio [HR] ϭ 0.821; 95% CI, 0.673 to 1.001; P ϭ .051) per the primary analysis of unstratified log-rank test (P ϭ .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P ϭ .049). Within the IFN-␣ group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-␣ (P Ͻ .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-␣ (P Ͻ .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%). ConclusionSunitinib demonstrates longer overall survival compared with IFN-␣ plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.