Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-3 trial in 3^rd and 4^th line subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 5.6 months (mos) for T compared to 3.9 mos for sorafenib (S) (p = 0.017, HR = 0.73). Methods: Subjects with mRCC 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; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. Pre-specified subgroups included prior treatment, IMDC prognostic group, and demographic characteristics. Results: Tivozanib demonstrated PFS benefit in all subgroups including men, women, patients over 65, and under 65. The hazard ratio was the same for patients enrolled in North America and the EU. Patients with ECOG performance status (PS) of 0 had a lower HR than patients with ECOG PS of 1. There was an increase in HR from IMDC favorable vs IMDC intermediate vs IMDC poor. PFS favored tivozanib in patients who had two prior lines of therapy, those treated with three prior lines, those with a prior checkpoint inhibitor, or with two prior VEGFR TKIs. Conclusions: Tivozanib improved PFS vs. sorafenib across several subgroups in TIVO-3. Patients with favorable and intermediate IMDC risk and ECOG PS 0 seemed to derive the most benefit. Patients treated with a prior checkpoint inhibitor or two VEGFR-TKIs had a longer PFS than patients treated on sorafenib. Clinical trial information: NCT02627963