Background
Phase III, open-label RCT. 350 patients with refractory advanced RCC who had received ≥2 prior lines of therapy including at least one VEGF-targeted therapy. Tivozanib (selective VEGFR1/2/3 inhibitor) compared to sorafenib (approved in this setting). Enrolled in North America, Europe, and Australia — a truly later-line RCC population.
Interventions and follow up
Arm A: Tivozanib 1.5mg/day orally (3 wks on / 1 wk off)
Arm B: Sorafenib 400mg twice daily orally
Primary endpoint: PFS
mFollow up: 18.8 mo
Arm B: Sorafenib 400mg twice daily orally
Primary endpoint: PFS
mFollow up: 18.8 mo
Results
PFS: 5.6 vs 3.9 mo, HR 0.73, P=.016
OS: 16.4 vs 19.2 mo, HR 1.12, P=.37 — not significant (reverse trend)
ORR: 18% vs 8%
Disease control rate: 74% vs 58%
OS: 16.4 vs 19.2 mo, HR 1.12, P=.37 — not significant (reverse trend)
ORR: 18% vs 8%
Disease control rate: 74% vs 58%
Adverse events
Overall: Grade ≥3 AEs 52% vs 55%; discontinuation due to AEs 10% vs 17%
Cardiovascular: Hypertension grade ≥3 20% vs 14%
Dermatologic: Hand-foot skin reaction (any) 16% vs 34%
GI/constitutional: Diarrhea grade ≥3 3% vs 7%; fatigue 14% vs 17%
Cardiovascular: Hypertension grade ≥3 20% vs 14%
Dermatologic: Hand-foot skin reaction (any) 16% vs 34%
GI/constitutional: Diarrhea grade ≥3 3% vs 7%; fatigue 14% vs 17%
Conclusions
Tivozanib significantly improved PFS and ORR versus sorafenib in heavily pretreated RCC, with a more favorable tolerability profile particularly for hand-foot skin reaction. The OS signal was non-significant and trended in favor of sorafenib, likely due to post-progression crossover dynamics, not true harm from tivozanib.
Key Limitations
Key Limitations: OS trended toward sorafenib (HR 1.12), likely explained by significantly more patients crossing over from sorafenib to tivozanib post-progression (48%) than from tivozanib to sorafenib (23%), diluting the OS signal. This crossover imbalance is a critical confound. The primary endpoint is PFS — a surrogate in RCC. The trial enrolled an immunotherapy-naïve population (pre-2015 era), raising questions about applicability in patients who have previously received IO-based combinations.
Clinical Context
FDA approved tivozanib for relapsed/refractory RCC in 2021 based on TIVO-3. The favorable tolerability versus sorafenib (particularly less hand-foot toxicity) makes it an attractive option in later-line settings. In the modern treatment landscape, most patients will have received IO + VEGF-TKI combinations in first line; tivozanib's role is primarily 3L+ after progression on immune checkpoint inhibitor-containing regimens. The reversed OS trend should be contextualized as a crossover artifact.
References
References: Rini BI et al, Lancet Oncol 2020