TIVO-3: A Phase 3, Randomised, Open-Label Study Comparing Tivozanib to Sorafenib in Patients with Advanced Renal Cell Carcinoma

Abstract

Background: Treatment for renal cell carcinoma (RCC) has been revolutionised by vascular endothelial growth factor receptor (VEGFR) inhibitors. TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) versus sorafenib as third- or fourth-line therapy for metastatic RCC. Methods: Patients with metastatic RCC with at least two prior systemic treatments, including at least one prior VEGFR inhibitor, were stratified by IMDC risk category and type of prior therapy, then randomised 1:1 to either tivozanib 1·5 mg orally once daily in 4-week cycles (21 days on treatment followed by 7 days off treatment) or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival; key secondary endpoints were objective response rate, overall survival, and safety. Findings: 350 patients were randomly assigned to tivozanib or sorafenib. Median progression-free survival was significantly longer for tivozanib (5·6 months) than sorafenib (3·9 months; hazard ratio [HR] 0·73 [95% CI 0·56-0·94], p=0·0165). Objective response rate was higher for tivozanib than sorafenib (18% vs 8%; p=0·0168). At the time of this analysis, preliminary overall survival was not significantly different (HR 1·12 [95% CI 0·84-1·51], p=0·437). The most common treatment-related adverse events were hypertension (36%), diarrhoea (33%), and fatigue (29%) for tivozanib and diarrhoea (50%), palmar-plantar erythrodysesthesia syndrome (38%), and hypertension (25%) for sorafenib. Adverse events led to fewer dose interruptions (48% vs 63%, p=0·007) and reductions (24% vs 38%, p=0·005) for tivozanib versus sorafenib. No treatment-related deaths were reported. Interpretation: Tivozanib demonstrated improved progression-free survival versus sorafenib as third- or fourth-line therapy for metastatic RCC. Tivozanib was better tolerated than sorafenib, with fewer dose reductions and interruptions, and is the first to demonstrate clinical benefit in a third-line or later setting in RCC. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT02627963. Funding Statement: This study was sponsored by AVEO Oncology. Declaration of Interests: BIR has received research funding from Peloton, and research funding and and honoraria from AVEO, Pfizer, Bristol-Myers Squibb, and Merck. SKP has received honoraria from and served as a consultant to Pfizer, Novartis, AVEO, Genentech, Exelixis, Bristol-Myers Squibb, Astellas, Eisai, Roche, and Ipsen. BJE has received research funding from AVEO, Bristol-Myers Squibb and Novartis, and honoraria from Bristol-Myers Squibb, Roche, Pfizer, Oncorena, AVEO, and Ipsen. MBA has served as an advisor to and received honoraria from AVEO, Merck, Bristol-Myers Squibb, Eisai, Pfizer, Exelixis, Roche, Novartis, and Arrowhead. TEH has served as an advisor to Pfizer, Exelexis, Bristol-Myers Squibb, AVEO, and Janssen. CP has served as a consultant to and on the speakers’ bureaus of EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis, and General Electrics, and honoraria from Roche. EV has served as an advisor to and on the speakers’ bureaus of Eusa Pharma, Pfizer, Novartis, Bristol-Myers Squibb, Merck, and Ipsen. MNN is an employee of AVEO. DFM has served as an consultant to Array BioPharm, Genentech, Alkermes, Inc., Jounce Therapeutics, Peloton, EMD Serono and Eli Lilly, received research funding from X4 Pharma, Prometheus, Genentech and Alkermes, and has served as a consultant to and received research funding from Bristol-Myers Squibb, Pfizer, Merck, Novartis, and Exelius. Ethics Approval Statement: This trial was approved by the institutional review board or ethics committee at every centre and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any trial procedure.