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Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre,
Brian I Rini1, Sumanta K Pal2, Bernard J Escudier3
1Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
Background:
Treatment for renal cell carcinoma has been revolutionised by inhibitors of VEGF receptor. Previous studies have suggested that treatment with a VEGF receptor (VEGFR) tyrosine kinase inhibitor might be effective in patients who had previous checkpoint inhibitor therapy. Therefore, TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) with those of sorafenib as third-line or fourth-line therapy in patients with metastatic renal cell carcinoma.
Methods:
In this open-label, randomised, controlled trial done at 120 academic hospitals in 12 countries, we enrolled eligible patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments (including at least one previous treatment with a VEGFR inhibitor), measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received previous treatment with tivozanib or sorafenib. Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy and randomised (1:1) with a complete permuted block design (block size of four) to either tivozanib 1·5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Investigators and patients were not masked to treatment. The primary endpoint was progression-free survival by independent review in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02627963.
Findings:
Between May 24, 2016, and Aug 14, 2017, 350 patients were randomly assigned to receive tivozanib (175 patients) or sorafenib (175 patients). Median follow-up was 19·0 months (IQR 15·0-23·4). Median progression-free survival was significantly longer with tivozanib (5·6 months, 95% CI 5·29-7·33) than with sorafenib (3·9 months, 3·71-5·55; hazard ratio 0·73, 95% CI 0·56-0·94; p=0·016). The most common grade 3 or 4 treatment-related adverse event was hypertension (35 [20%] of 173 patients treated with tivozanib and 23 [14%] of 170 patients treated with sorafenib). Serious treatment-related adverse events occurred in 19 (11%) patients with tivozanib and in 17 (10%) patients with sorafenib. No treatment-related deaths were reported.
Interpretation:
Our study showed that tivozanib as third-line or fourth-line therapy improved progression-free survival and was better tolerated compared with sorafenib in patients with metastatic renal cell carcinoma.
Funding:
AVEO Oncology.
Insights
Tivozanib significantly improved progression-free survival in patients with metastatic renal cell carcinoma compared to sorafenib. This potent VEGF receptor (VEGFR) inhibitor demonstrated better tolerability in third- or fourth-line therapy settings.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic renal cell carcinoma (mRCC) treatment has advanced with VEGF receptor inhibitors.
- Prior research suggests VEGFR inhibitors may benefit patients post-checkpoint inhibitor therapy.
- The TIVO-3 trial investigated tivozanib versus sorafenib in advanced mRCC.
Purpose of the Study:
- To compare the efficacy and safety of tivozanib and sorafenib.
- To evaluate tivozanib as a third-line or fourth-line treatment option for mRCC.
- To assess progression-free survival (PFS) in patients with advanced mRCC.
Main Methods:
- An open-label, randomized, controlled trial (TIVO-3) involving 350 patients with mRCC.
- Patients received either tivozanib (VEGFR inhibitor) or sorafenib.
- Primary endpoint was independent review of progression-free survival.
Main Results:
- Tivozanib showed a significantly longer median progression-free survival (5.6 months) than sorafenib (3.9 months).
- Hypertension was the most common Grade 3/4 adverse event for tivozanib (20%) and sorafenib (14%).
- Serious adverse events were comparable between tivozanib (11%) and sorafenib (10%), with no treatment-related deaths.
Conclusions:
- Tivozanib improves progression-free survival in patients with metastatic renal cell carcinoma.
- Tivozanib is better tolerated than sorafenib in the third- or fourth-line setting.
- Tivozanib represents a valuable therapeutic option for advanced mRCC patients previously treated with systemic therapies.
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