Results from the Phase III TIVO-1 trial (TIvozanib Versus sOrafenib in 1st line advanced RCC) demonstrating the safety and tolerability profile of tivozanib (AVEO Oncology)versus sorafenib in the first line setting for patients with metastatic renal cell carcinoma (RCC) were presented at the ESMO 2012 Congress (European Society for Medical Oncology) in Vienna, Austria (September 28 – October 2, 2012).

Advanced RCC, or kidney cancer, is the ninth most commonly diagnosed cancer in men and women in the U.S.8 Worldwide it is estimated that more than 250,000 people are diagnosed and more than 100,000 people die from the disease each year.9 RCC accounts for more than 90 percent of all kidney cancers.[10] Currently available therapies provide less than one year of median PFS in treatment na?ve patients and are associated with significant toxicities.[11] These toxicities not only lead to high rates of dose reductions and interruptions (potentially compromising efficacy), but also can impact a patient?s quality of daily living.[12]

New treatment option

Tivozanib is the first investigational compound to demonstrate a combination of statistically significant PFS and tolerability in a pivotal study for advanced RCC versus an approved targeted agent, sorafenib. Tivozanib is a potent, selective and long half-life inhibitor of all three vascular endothelial growth factor (VEGF) receptors that is designed to optimize VEGF blockade while minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. Tivozanib is an oral, oncedaily, investigational tyrosine kinase inhibitor (TKI) for which positive results from a Phase IIIclinical study in advanced RCC have been reported, and is being evaluated in other tumors.

TIVO-1: Tivozanib compared to Sorafenib

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TIVO-1 is a global, randomized Phase IIIsuperiority 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 superiority pivotal study in first-line advanced RCC that has demonstrated statistically significant and clinically meaningful PFS superiority versus an approved targeted agent (sorafenib) in advanced RCC. The TIVO-1 study has demonstrated that a potent, selective and long-half life inhibitor of all three VEGF receptors can result in superior efficacy and improved tolerability.[1]

Eighty-six centers participated in the TIVO-1 study, including centers in Europe and North America. The primary efficacy endpoint (PFS) was ascertained for each subject by a central panel of blinded independent radiologists. Patients randomized to the sorafenib arm of TIVO-1 were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression. No crossover protocol was available for patients randomized to the tivozanib arm.

Clinical data: TAURUS

The data presented shows that patients treated with tivozanib experienced fewer Grade 3 and off-target adverse events (AEs), stayed on treatment longer, and required fewer dose reductions and interruptions compared with those treated with sorafenib.[1] Also presented were the first tivozanib biomarker data in RCC, and the design of the TAURUS (TivozAnib Use veRsUs Sunitinib in advanced renal cell carcinoma) patient preference study, in which the first patient has now been enrolled.

AVEO recently submitted a New Drug Application to the U.S. Food and Drug Administration seeking approval for tivozanib. ?Minimizing toxicities associated with anti-VEGF therapy is a vital consideration in RCC. Adverse events have been shown to contribute to dose reductions, interruptions and discontinuations of anti-VEGF therapy,? noted Timothy Eisen, Ph.D., FRCP, study investigator, Cambridge University Health Partners. ?The data from TIVO-1 show that treatment with tivozanib led to fewer side effects and lower rates of dose modifications than with sorafenib. This suggests that it is easier to maintain full dose therapy with tivozanib.?

The TIVO-1 global, randomized Phase III clinical trial compared the safety and tolerability of tivozanib and sorafenib in 517 patients with advanced RCC. Results of the trial were presented at the ASCO Annual Meeting earlier this year and showed that tivozanib demonstrated a statistically significant improvement in progression-free survival (PFS) compared with sorafenib in the overall patient population (median PFS 11.9 months versus 9.1 months; p=0.042, HR=0.797). Further, in a pre-specified subset of RCC patients who were treatment-na?ve, tivozanib demonstrated a statistically significant improvement in PFS with a median of 12.7 months compared with 9.1 months for sorafenib (p=0.037;HR=0.75), making tivozanib the first treatment to demonstrate a median PFS of greater than one year in this patient population.[2]

Tivozanib is an investigational drug being evaluated for first-line treatment of advanced RCC.

Investigators evaluated drug-related AEs versus sorafenib with the goal of better understanding the tivozanib safety profile. The results of the safety analysis showed:

  • Investigator-reported adverse events for tivozanib showed lower rates of dose reductions, interruptions, and discontinuations compared to sorafenib: dose reductions (11.6% vs. 42.8%, p<0.001), interruptions (17.8% vs. 35.4%, p<0.001), and discontinuations (4.2% vs. 5.4%)1
  • Drug-related AEs occurred in fewer patients on tivozanib than patients on sorafenib (67.6% vs. 83.3%)1
  • Fewer patients in the tivozanib group had ?Grade 3 drug-related AEs than patients in the sorafenib group (36.3% vs. 51.0%, respectively).[1] ?Grade 3 hypertension, an established ontarget effect of angiogenesis inhibitors, was more common in the tivozanib group (23.6% vs. 15.2%), and ?Grade 3 hand-foot syndrome (1.9% vs. 16.7%), diarrhea (1.9% vs. 5.8%) and lipase elevation (0.8% vs. 5.8%) were more common in the sorafenib group.[1]

?Our tivozanib development program in RCC is comprehensive and ongoing. With positive safety and efficacy data from TIVO-1 in-hand, we continue to explore the role of biomarkers and patient preference with the ultimate goal of helping clinicians optimize RCC treatment,? said William Slichenmyer, M.D., Sc.M., chief medical officer at AVEO. ?Additional analyses from our ongoing biomarker program will be presented at future congresses and our TAURUS patient preference study vs. Sutent? (sunitinib) is now underway.?

In addition to detailed safety results, pharmacokinetic/pharmacodynamic data from TIVO-1 were also presented.[3]

Tivozanib exposure, blood pressure
Analyses were conducted using pooled data from patients in AVEO?s randomized placebo-controlled PhaseII study of tivozanib in RCC and from the TIVO-1 study to explore the relationship between tivozanib exposure, blood pressure and sVEGFR2.[3]

Patients in the analysis showed a median increase in diastolic blood pressure of 5mm Hg compared with
baseline, and also experienced a decrease in sVEGFR2 corresponding to tivozanib exposure.[3]
Hypertension and sVEGFR are known to be on-target biomarkers of activity and clinical outcome.[4,5,6] ?One of our goals in becoming a global Category Leader in oncology is to develop precision medicines that revolutionize the methods used to treat patients with cancer,? said Stephen Eck, M.D., Ph.D., Vice President of Medical Oncology, Astellas Pharma Global Development. ?We believe the data showing the combination of tivozanib?s statistically significant PFS and its tolerability profile represents a potentially important advancement in the treatment of this disease.?

Pastient Preference
A review of the clinical study design of TAURUS, a randomized (1:1), double-blind, crossover controlled, multi-center Phase 2 study c
omparing tivozanib versus sunitinib in approximately 160 patients with advanced RCC who have received no prior systemic therapy was presented at the meeting. The primary objective of the study is to compare patient preference for tivozanib or sunitinib.

The first patient has been enrolled in TAURUS, and the study will continue to enroll patients at sites throughout the United States and Western Europe.

For more information:
Title: Detailed Comparison of the Safety of Tivozanib Versus Sorafenib in Patients with Advanced/Metastatic Renal Cell Carcinoma (mRCC) from a PhaseIII Trial
Date/Poster/Location: Oct. 1, 1:00-2:00pm CET / 7:00-8:00am ET; Poster #795PD; Hall F2

Title: Tivozanib Pharmacokinetic/Pharmacodynamic Analysis of Blood Pressure and Soluble Vascular Endothelial Growth Factor Receptor 2 (sVEGFR2) in Patients with Advanced Renal Cell Carcinoma
Date/Poster/Location: Oct. 1, 1:00-2:00pm CET / 7:00-8:00am ET; Poster #796PD; Hall F2

Title: Patient Preference for Tivozanib Hydrochloride or Sunitinib in the Treatment of Metastatic Renal Cell Carcinoma (mRCC): TAURUS study
Date/Poster/Location: Sep. 29, 1:00-2:00pm CET / 7:00-8:00am ET; Poster #892TiP; Hall XL

[1] Eisen T, Sternberg CN et al.
Detailed comparison of the safety of tivozanib hydrochloride versus sorafenib in patients with
advanced/metastatic renal cell carcinoma (mRCC ) from a Phase III trial. ESMO 2012 Congress (Poster 795PD)
[2] Motzer RJ, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open label, multicenter trial. J Clin Oncol 2012;30 (suppl; abstr 4501)
[3] Nosov DA, Motzer RJ, et al. Tivozanib pharmacokinetic/pharmacodynamic analysis of blood pressure and soluble vascular endothelial growth factor receptor 2 (sVEGFR2) in patients with advanced renal cell carcinoma. ESMO 2012 Congress (Poster 796PD)
[4] De Primo SE, Bello CL, Smeraglia J et al. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF related proteins. J Transl Med 2007;5:32.
[5] Hutson T, Davis ID, Macheils JH et al. Biomarker analysis and final efficacy and safety results of a phase II renal cell carcinoma trial with pazopanib (GW786034), a multi-kinase angiogenesis inhibitor. J Clin Oncol 2008;26:Abstract 5046.
[6] Rini BI, Michaelson D, Rosenberg JE et al. Antitumor activity and biomarker analysis of sunitinib in patients with
bevacizumab-refracory metastatic renal cell carcinoma. J Clin Oncol 2008;26:3743?3748.
[7] Escudier B, Steelman L et al. Patient preference for tivozanib hydrochloride or sunitinib in the treatment of metastatic renal cell carcinoma (mRCC ): TAURUS study. ESMO 2012 Congress (Poster 892TiP)
[8] 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: .
[9] Cancer Research UK. Worldwide Cancer Statistics.
[10] American Cancer Society.General Data
[11] Bhargava, P., Robinson, M. Development of second-generation VEGFR tyrosine kinase inhibitors: current status. Curr Oncol Rep 2011 Apr;13(2):103-11
[12] Ravaud, A. How to optimise treatment compliance in metastatic renal cell carcinoma with targeted agents. Annals of Oncology 20 (Supplement 1): i7?i12, 2009

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