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Why AVEO Pharmaceuticals' Tivozanib Will Be Approved For The Treatment Of Advanced Renal Cell Carcinoma

By Robert Schwartz :

AVEO Pharmaceuticals ( AVEO ) was founded as Genpath Pharmaceuticals in 2001 in Cambridge, Massachusetts. The company engages in the discovery and development of targeted cancer therapies. AVEO's most advanced pipeline asset is tivozanib, a low-molecular-weight inhibitor of the VEGF receptor for which a marketing application for the treatment of metastatic renal cell carcinoma ((RCC)) was filed in September 2012.

The Phase-III results for tivozanib in RCC were reported in January 2012. The trial, known as TIVO-1, evaluated the comparative efficacy and safety of tivozanib relative to sorafenib in 517 patients with RCC. TIVO-1 was the first registrational study in 1st-line RCC to compare an investigational agent against an approved VEGF therapy . Based on independent radiological reviews, tivozanib demonstrated a statistically-significant improvement in progression-free survival (( PFS )) with a median PFS (primary endpoint) of 11.9 months compared to a median PFS of 9.1 months for sorafenib in the intent-to-treat population (HR=0.797, 95% CI 0.639-0.993; P=0.042). Tivozanib's investigators reported a median PFS of 12.7 months which is the longest ever reported for a Phase III trial in treatment-naïve RCC . The objective response rate (ORR) for tivozanib was 33% compared to 23% for sorafenib (P=0.014).

The efficacy advantage of tivozanib over sorafenib was consistent across subgroups in the study. In treatment-naïve patients advanced RCC (70% of total 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 (HR 0.756, 95% CI 0.580-0.985; P=0.037).

In the subpopulation of patients who were pretreated with systemic therapy including cytokines (30% of total study population), PFS for tivozanib and sorafenib were 11.9 months and 9.1 months, respectively. These results were not statistically significant.

With respect to overall survival (( OS )), there were a total of 219 deaths, 118 and 101 in the tivozanib and sorafenib arms, respectively. A trend toward longer OS was observed in the sorafenib arm compared with the tivozanib arm (median OS in the tivozanib arm was 28.8 months vs. 29.3 months in the sorafenib arm; HR=1.25, P =0.105).

The OS comparison between study arms was confounded by differential use of next-line cancer therapies. This was expected based on the study's one-way crossover to the experimental therapy after disease progression in the control arm. Significant enrollment in Central and Eastern Europe may have contributed to this result, as access to subsequent effective treatment options for RCC are limited in this region. In North America/Western Europe, a trend toward longer OS was observed with tivozanib compared to sorafenib (HR=0.503; P =0.195); median OS was not reached at the time of analysis in either arm. In the context of overall survival, it must be noted that of the pivotal trials with agents approved for the treatment of RCC since 2005, six of seven failed to show a survival benefit(Table) .

Drugs Approved for the Treatment of Renal CellCarcinoma

Drug Brand Name Approved Indication Study Design Clinical Endpoint(s)
Sorafenib Nexavar 2005 Advanced RCC sorafenib vs. placebo in 2nd-line patients PFS for full approval ; no OS benefit
Sunitinib Sutent 2006 First-line metastatic RCC IFN vs. sunitinib PFS for full approval ; no OS benefit
Temsirolimus Torisel 2007 First-line metastatic RCC IFN vs. IFN ± temsirolimus OS benefit for temsirolimus vs. IFN;No OS benefit for low-dose temsirolimus + IFN
Bevacizumab Avastin 2009 First-line metastatic RCC IFN ± bevacizumab PFS for full approval ; no OS benefit
Pazopanib Votrient 2009 First-line metastatic RCC pazopanib vs. placebo PFS benefit for full approval ; no OS benefit
Everolimus Afinitor 2009 Metastatic RCC following failure with sunitinib or sorafenib everolimus vs. placebo PFS for full approval
Axitinib Inlyta 2012 Metastatic RCC following failure with one systemic therapy axitinib vs. sorafenib PFS for full approval ; no OS benefit
Tivozanib First- & second- line metastatic RCC tivozanib vs. sorafenib PFS for full approval ; no OS benefit

With respect to safety , the adverse event profile of tivozanib was superior to sorafenib . Dose reductions were needed in 11.6% of the tivozanib group versus 42.8% of the sorafenib group (P<.001 interruptions="" occurred="" in="" of="" the="" tivozanib="" group="" versus="" sorafenib="" and="" discontinuations="" group.="" overall="" there="" were="" fewer="" drug-related="" adverse="" events="" arm:="" hypertension="" was="" most="" frequent="" event="" related="" to="" treatment="" with="" grade="" or="" higher="" vs.="" is="" an="" established="" on-target="" effect="" angiogenesis="" inhibitors="" this="" study="" it="" easily="" managed="" standard="" anti-hypertensives.="" as="" compared="" arm="" patients="" also="" experienced="" more="" dysphonia="" but="" less="" diarrhea="" hand-foot="" syndrome="" alopecia.="">

Overall, and particularly in the context of the recent history of drugs approved for the treatment of advanced RCC, it is difficult to conceive of circumstances that would preclude the approval of tivozanib. An advisory committee of the FDA is scheduled to review the tivozanib data on May 2, 2013 and a final decision expected by/on July 28, 2013.

In addition to tivozanib, AVEO has a pipeline of monoclonal antibodies that includes ficlatuzumab, an antibody that inhibits hepatocyte growth factor and is currently in Phase II development for the treatment of non-small cell lung cancer, and AV-203, an antibody targeting the ErbB3 receptor that is currently being evaluated in a Phase I study.

AVEO has strategic partnerships with Merck, OSI Pharmaceuticals, Kyowa Hakko Kirin, Astellas, and Biogen Idec. With respect to tivozanib, Kyowa Hakko Kirin has marketing rights in Asia, Astellas has ex-U.S. rights excluding Asia, and AVEO has retained rights to North America.

As of December 31, 2012, the company had cash and short-term equivalents totaling $160 MM and an annual burn rate of ~$130 MM/year. The burn rate is anticipated to decrease now that TIVO-1 has been completed.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

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The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.


The views and opinions expressed herein are the views and opinions of the author and do not necessarily reflect those of Nasdaq, Inc.

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