Clinical question: In heavily pretreated metastatic RCC, does tivozanib improve disease control versus sorafenib?
Design: Phase III randomized open-label trial; 350 patients with metastatic RCC after 2–3 prior systemic regimens, including prior VEGFR-TKI therapy. Primary endpoint PFS by blinded independent review.
Median PFS 5.6 vs 3.9 months; HR 0.73 (95% CI 0.56–0.95), P=.02.
2-year PFS absolute difference 13 points; approximate NNT ≈ 8 at 2 years for remaining progression-free. This is a landmark/time-to-event NNT and should not be confused with an NNT based on median PFS.
ORR 18% vs 8%, absolute increase 10 points; NNT = 10 for one additional objective response.
Final OS analysis did not demonstrate an OS advantage; reported HR approximately 0.97. Grade 3 treatment-related adverse events occurred in 44% vs 55%; dose reduction 24% vs 38%, interruption 48% vs 63%, discontinuation 21% vs 29%.
Open-label phase III trial with blinded independent radiological PFS assessment. Patients were heavily pretreated and included prior checkpoint-inhibitor exposure. Because PFS was the primary endpoint, the absolute-effect interpretation focuses on PFS and response rather than forcing an OS NNT.
TIVO-3 demonstrates a real late-line PFS and response advantage with tivozanib, including a striking 13-point difference in 2-year PFS. The absence of an OS improvement means the treatment should be understood as a disease-control strategy rather than a proven survival-extending intervention in this trial.
TIVO-3 studied tivozanib versus sorafenib in patients who had received at least two prior systemic treatments, including at least one VEGFR inhibitor; this is a third-/fourth-line trial, not a trial formally named “TIVO-4.” Median PFS was 5.6 vs 3.9 months (HR 0.73, 95% CI 0.56–0.94). Final OS was not different (HR 0.97, 95% CI 0.75–1.24).
Prior first-line immunotherapy: A subset had prior checkpoint inhibitor exposure, and tivozanib retained activity in this heavily pretreated population. This supports VEGFR-TKI activity after prior agents; it should not be read as evidence that continuing/rechallenging ICI is beneficial. CONTACT-03 and TiNivo-2 directly tested ICI rechallenge and did not show added benefit.
TIVO-3 primary report ↗ · Final OS report ↗ · EAU RCC guidance ↗
Targeted freshness note added 14 October 2026; full guideline reconciliation remains pending.