Background: Tivozanib (T) is a potent and highly selective VEGFR inhibitor. TIVO-3 is a phase 3 study designed to compare the efficacy and safety of T with those of sorafenib (S) as 3rd and 4th line therapy in patients with metastatic RCC. Methods: Subjects with RCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint inhibitor (CPI); TKI plus other) then randomized in a 1:1 ratio to T or S. Results: The 2 arms were well balanced for demographics and prior cancer history. 60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 26% had prior treatment with a CPI. Patients treated with T demonstrated PFS superiority compared to S, 5.6 (95% CI 7.3 - 5.3) v. 3.9 mos (95% CI 5.6 – 3.7; HR 0.73; p=0.02). ORR was 18% for T compared to 8% for S (p=0.02). 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. The predefined, interim analysis for OS performed two years after enrollment was closed had a HR of 0.99 based on 227 events. The final analysis will be presented based on an estimate of 263 events. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this heavily-treated/relapsed or refractory RCC population and is better tolerated than S. Final OS data will be updated prior to presentation. Clinical trial information: 02627963.