On March 10, 2021, the VEGF tyrosine kinase inhibitor tivozanib was approved for treatment of adults with relapsed or refractory advanced renal cell carcinoma following at least two prior systemic therapies.1,2
Supporting Efficacy Data
Approval was based on findings in the open-label, phase III TIVO-3 trial (ClinicalTrials.gov identifier NCT02627963).2,3 In the trial, 350 patients with relapsed or refractory advanced renal cell carcinoma who had received two or three prior systemic treatments—including at least one VEGFR kinase inhibitor other than sorafenib or tivozanib—were randomly assigned to receive oral tivozanib at 1.34 mg once daily for 21 consecutive days every 28 days (n = 175) or sorafenib at 400 mg twice a day continuously (n = 175) until disease progression or unacceptable toxicity. The main outcome measure was progression-free survival on blinded independent radiology review committee assessment.
Median progression-free survival was 5.6 months (95% confidence interval [CI] = 4.8–7.3 months) in the tivozanib group vs 3.9 months (95% CI = 3.7–5.6 months) in the sorafenib group (hazard ratio [HR] = 0.73, 95% CI = 0.56–0.95, P = .016). Median overall survival was 16.4 months (95% CI = 13.4–21.9 months) in the tivozanib group vs 19.2 months (95% CI = 14.9–24.2 months) in the sorafenib group (HR = 0.97, 95% CI = 0.75–1.24). The overall response rate was 18% vs 8%, with median durations of response of not reached (95% CI = 9.8 months to not estimable) vs 5.7 months (95% CI = 5.6 months to not estimable).
How It Works
Tivozanib is a tyrosine kinase inhibitor. In vitro cellular kinase assays demonstrated that tivozanib inhibits phosphorylation of VEGFR-1, VEGFR-2, and VEGFR-3 and inhibits other kinases including c-kit and PDGFRβ at clinically relevant concentrations. Tivozanib inhibited angiogenesis, vascular permeability, and tumor growth of various tumor cell types, including human renal cell carcinoma in tumor xenograft models in mice and rats.
How It Is Used
The recommended dose of tivozanib in the current indication is 1.34 mg once daily for 21 consecutive days every 28 days until disease progression or unacceptable toxicity.
If dose modifications are required for adverse reactions, the dose should be reduced to 0.89 mg for 21 consecutive days every 28 days. Medical management for diarrhea, nausea, or vomiting should be initiated prior to dose interruption or reduction.
Prescribing information provides instructions on dosage modification—including dose reduction and withholding and discontinuing treatment—for adverse reactions including grade 3 or 4 hypertension, grade 3 or 4 cardiac failure, arterial thrombotic events, grade 3 or 4 hemorrhagic events, proteinuria, reverse posterior leukoencephalopathy syndrome, and other adverse reactions. Treatment should be permanently discontinued for grade 4 hypertension, grade 4 cardiac failure, any-grade arterial thrombotic events, grade 3 or 4 hemorrhagic events, nephrotic syndrome, any signs/symptoms of reverse posterior leukoencephalopathy syndrome (of any grade), and any other grade 4 adverse reaction.
The recommended dose in patients with moderate hepatic impairment is 0.89 mg once daily for 21 days on treatment followed by 7 days off every 28-day cycle. Use of tivozanib should be avoided in patients with severe hepatic impairment. Concomitant use with strong CYP3A inducers (eg, phenobarbital, phenytoin, rifampicin) should be avoided.
Among patients who received tivozanib in TIVO-3, 53% were exposed to treatment for at least 6 months and 31% for more than 1 year.
In TIVO-3, the most common adverse events of any grade (≥ 20%) in the tivozanib group were fatigue (67% vs 48% in sorafenib group), hypertension (44% vs 31%), diarrhea (43% vs 54%), decreased appetite (39% vs 30%), nausea (30% vs 18%), dysphonia (27% vs 9%), hypothyroidism (24% vs 11%), cough (22% vs 15%), and stomatitis (21% vs 23%). Grade 3 or 4 adverse events occurred in 67% of the tivozanib group vs 72% of the sorafenib group, with the most common in the tivozanib group being hypertension, fatigue, and decreased appetite. Any-grade bleeding occurred in 17% of the tivozanib group. The most common grade 3 or 4 laboratory abnormalities in the tivozanib group were decreased sodium, increased lipase, decreased phosphate, and decreased lymphocytes.
Serious adverse events occurred in 45% of patients in the tivozanib group, with the most common being bleeding, venous thromboembolism, arterial thromboembolism, acute kidney injury, and hepatobiliary disorders. Adverse events led to dose interruption in 48% of patients and to dose reduction in 24%. Adverse events led to permanent discontinuation of treatment in 21%. Fatal adverse events occurred in 8% of patients.
Tivozanib has warnings/precautions for hypertension and hypertensive crisis, cardiac failure, cardiac ischemia and arterial thromboembolic events, venous thromboembolic events, hemorrhagic events, proteinuria, thyroid dysfunction, risk of impaired wound healing, reversible posterior leukoencephalopathy syndrome, embryofetal toxicity, and allergic reactions to tartrazine (FD&C Yellow No. 5, contained in the 0.89-mg capsule of tivozanib).
Blood pressure should be controlled prior to starting tivozanib. Thyroid function should be assessed prior to initiating treatment. Patients must be monitored throughout treatment for hypertension, signs or symptoms of cardiac failure, proteinuria, and thyroid function. Close monitoring throughout treatment is necessary for patients at increased risk of cardiac ischemia and arterial thromboembolic events or venous thromboembolic events and for patients who are at risk for or who have a history of bleeding. Tivozanib should be withheld for at least 24 days before elective surgery and not given for at least 2 weeks following major surgery and adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established.
Patients should be advised not to breastfeed while receiving tivozanib. Females and males of reproductive potential should be advised that treatment may impair fertility.
1. U.S. Food and Drug Administration: FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-tivozanib-relapsed-or-refractory-advanced-renal-cell-carcinoma. Accessed March 29, 2021.
2. Fotivda (tivozanib) capsules prescribing information, AVEO Pharmaceuticals, Inc., March 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212904s000lbl.pdf. Accessed March 29, 2021.
3. Rini BI, Pal SK, Escudier BJ, et al: Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): A phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol 21:95-104, 2020.