Tivozanib (AV-951)
Tivozanib: Lead Product Candidate Being Evaluated as First-Line Therapy for Advanced RCC
Advanced RCC, or kidney cancer, is the ninth most commonly diagnosed cancer in men and women in the U.S.1 Worldwide it is estimated that more than 250,000 people are diagnosed and more than 100,000 people die from the disease each year2. RCC accounts for 90 percent of all malignant kidney tumors3. Despite advances in RCC therapies, significant unmet need persists.
Patients are invited to visit www.clinicaltrials.gov for more information regarding tivozanib clinical trials, or contact AVEO’s medical affairs department at medicalaffairs@aveopharma.com.
Tivozanib Successfully Demonstrated Progression-Free Survival Superiority over Sorafenib in TIVO-1 Trial
In January 2012, AVEO and its collaborator Astellas Pharma Inc. announced that tivozanib successfully demonstrated superiority over sorafenib in the primary endpoint of progression-free survival (PFS) in TIVO-1, a global, randomized Phase 3 clinical trial evaluating the efficacy and safety of investigational drug tivozanib compared to sorafenib in 517 patients with advanced RCC.
TIVO-1 is the first registration study in first-line RCC that is comparing an investigational agent against an approved VEGF therapy. The trial is being led by Robert Motzer, M.D. from the Memorial Sloan-Kettering Cancer Center.
All patients in TIVO-1 had clear cell RCC, had undergone a prior nephrectomy, and had not previously been treated with either a VEGF or mTOR therapy. Based on the top-line analysis of events in TIVO-1, determined by a blinded, independent review committee, key top-line findings include:
- tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the overall study population
- tivozanib demonstrated a statistically significant improvement in PFS with a median PFS of 12.7 months compared to a median PFS of 9.1 months for sorafenib in the pre-specified subpopulation of patients who were treatment naïve (no prior systemic therapy); this subpopulation was approximately 70% of the total study population
- tivozanib demonstrated a well-tolerated safety profile consistent with the Phase 2 experience; the most commonly reported side effect was hypertension, a well established on-target and manageable effect of VEGFR inhibitors
In February 2011, AVEO and Astellas entered into a worldwide agreement outside of Asia to develop and commercialize tivozanib for the treatment of a broad range of cancers. AVEO and Astellas are evaluating tivozanib in additional clinical trials in other solid tumors.
Tivozanib Phase 2 Trial Showed Positive Safety and Efficacy Data
Prior to initiating TIVO-1, AVEO successfully completed a 272-patient, multi-center, randomized Phase 2 clinical trial of tivozanib in patients with advanced RCC. Median PFS achieved among all patients (n=272) in the Phase 2 trial was 11.7 months4.
The safety profile of tivozanib observed in the Phase 2 trial was notable for the minimal off-target toxicities often associated with VEGF, multi-targeted therapies. There was a low incidence of diarrhea, fatigue, stomatitis and hand-foot syndrome. Hypertension and dysphonia (hoarseness of voice), which are mechanism-related side effects associated with angiogenesis inhibitors, were the most commonly reported drug-related side effects, and both were manageable and reversible4.
BATON Clinical Development Program
In addition to TIVO-1 and other ongoing tivozanib clinical trials, AVEO and Astellas have initiated the BATON (Biomarker Assessment of Tivozanib in ONcology) program, a series of clinical trials assessing tivozanib biomarkers in solid tumors.
Screening patients throughout the treatment process for certain genetic biomarkers, including lactate dehydrogenase (LDH), vascular endothelial growth factor (VEGF) A, C and D, CD68, myeloid-derived gene signatures (MGS) and serum soluble cytokines, may help identify patients more likely to be responsive or resistant to therapy. The BATON program is designed to help guide the clinical development of tivozanib.
In December 2011, AVEO announced the initiation of patient enrollment in an open-label, multicenter, randomized Phase 2 clinical trial, called BATON-CRC, evaluating tivozanib in combination with modified FOLFOX6 (mFOLFOX6) compared to bevacizumab in combination with mFOLFOX6 as first-line therapy in patients with advanced metastatic colorectal cancer (CRC). BATON-RCC, a Phase 2 exploratory biomarker study in patients with advanced RCC, was initiated by AVEO in early 2011.
Tivozanib: A Potent, Selective and Continuous Inhibitor of All Three VEGF Receptors
Tivozanib is a potent, selective and continuous inhibitor of all three vascular endothelial growth factor (VEGF) receptors that is designed to optimize VEGF blockade while minimizing off-target toxicities. Tivozanib is an oral, once-daily, investigational tyrosine kinase inhibitor for which top-line results from a Phase 3 clinical study in advanced RCC have been reported, and is being evaluated in other tumors. AVEO is leveraging its Human Response Platform™ in order to enrich outcomes and minimize development risks for tivozanib.
- U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2007 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2010. Available at: www.cdc.gov/uscs.
- Cancer Research UK http://info.cancerresearchuk.org/cancerstats/world/the-global-picture/#Common; http://publications.cancerresearchuk.org/downloads/Product/cs_pdf_worldwide_2011.pdf
- Motzer RJ, et al. JCO 2009- Sutent.
- Nosov, D., et al. Poster presented at the ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 4550.