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ODAC to Review AVEO Oncology’s Investigational Drug Tivozanib in the Treatment of Renal Cell Carcinoma

In February 2013, AVEO Oncology and Astellas Pharma Inc. announced results from their controlled, multi-center, open-label, TIVO-1 study that compared the investigational VEGF inhibitor, tivozanib, head-to-head with the VEGF inhibitor, sorafenib [Nexavar; BayerHealthcare, Onyx Pharmaceuticals] in recurring or metastatic renal cell carcinoma. Patients (N=517) were randomized to tivozanib or sorafenib and must have undergone prior nephrectomy (complete or partial) for excision of the primary tumor.

On May 2, 2013, the FDA's Oncologic Drug Advisory Committee (ODAC) is meeting to discuss the efficacy and safety of tivozanib and will decide its fate. Seemingly, this is business as usual until a review of the dynamics in play makes ODAC’s yea or nay vote on tivozanib an interesting one to follow.

In the final analysis of TIVO-1, tivozanib demonstrated a statistically significant improvement in progression-free survival (PFS), the primary endpoint of the study, when compared with sorafenib: median PFS 11.9 months in the tivozanib arm vs 9.1 months for sorafenib. However, in the secondary endpoint that measured overall survival (OS), results showed that there was no statistical difference between the two arms. The final OS analysis shows a median OS of 28.8 months for tivozanib versus a median OS of 29.3 months for the sorafenib arm.

At first look, given the OS results, it would seem as if tivozanib did not perform any better (or worse) than its comparator; yet what is confounding the OS results is the fact that the TIVO-1 trial design allowed patients in the sorafenib arm to switch over to the tivozanib arm once their disease progressed. Roughly 74% of patients in the sorafenib arm received a subsequent therapy in the trial versus 36% in the tivozanib arm.

How ODAC will respond to a drug whose OS fared about the same as its comparator, but showed superiority in PFS brings the question of PFS vs OS as a gold standard under scrutiny once again. The validity of PFS and OS as endpoints has been debated before. Furthermore, crossover of patients in cancer clinical trials is a recognized phenomenon, confounding results, and casting shadows of doubt on trial endpoints.

In The Street, Adam Feuerstein is predicting a negative vote by the ODAC panel for recommendation to the FDA. He states, “Admittedly, my conviction level for this prediction isn't all that strong. Today's FDA seems addicted to approving all drugs, so the agency may be unwilling to subject tivozanib to the scrutiny it deserves. If the FDA takes it easy on tivozanib, the advisory panel may do the same.”

He is basing his prediction on the analysis of the OS data over a 2-year period in which the relative risk of death was 25% higher in the tivozanib arm vs the control arm. The greater risk of death between the 2 groups was not statistically significant. “That might work in Aveo's favor, but a hazard ratio of 1.245 against tivozanib is alarming -- even if not statistically significant -- and raises serious questions about the drug or the conduct of the study,” he states.

To read more click here: http://www.thestreet.com/story/11905026/1/why-aveos-kidney-cancer-drug-will-be-turned-down-by-next-weeks-fda-panel.html

Supporting the tivozanib recommendation by the ODAC committee is Aafia Chaudhry, MD. In an online article in PropThink, Dr. Chaudhry writes, “we see very little to suggest that a panel would vote against approval of this drug. While some may argue that the RCC market is crowded, we see tivozanib being used as an alternative to other oral therapies in the frontline setting. The agent’s beneficial dosing cycle and superior tolerability profile make this an exciting addition to the current armamentarium. We believe oncologists would want to have this available in the clinic to offer patients. It also adds a useful alternative to more toxic agents used in sequencing for subsequent lines of therapy.”

To read more click here: http://propthink.com/aveos-inflection-point-tivozanib-likely-to-receive-positive-advisory-vote-fda-approval/5898

Kimryn Rathmell, MD, PhD, Associate professor, The University of North Carolina, Chapel Hill, is a translational scientist and a medical oncologist dedicated to the care of patients with kidney cancer. According to Dr. Rathmell, “Going before ODAC, we have no clear OS advantage with tivozanib as compared with sorafinib, yet PFS is positively impacted at 8.4 months in the investigational arm.”

In patients who were treatment naïve (70% of total study population), tivozanib demonstrated a statistically significant improvement in PFS with a median of 12.7 months vs 9.1 months for sorafenib. According to the AVEO Oncology press release, “This is the longest median PFS reported to date in treatment-naïve advanced RCC patients in a pivotal study.”

In addition to meeting its endpoints, tivozanib demonstrated a good safety profile, with patients tolerating the drug well. The most common adverse event reported was hypertension which is consistent with the safety profile of the Phase 2 study. When asked about the possibility of ODAC not recommending the drug for FDA approval, Rathmell said, “This is a drug that has a strong PFS and a good side effect profile. It would be disappointing to go back to a Phase 3 trial because of a crossover.”

In the United States, kidney cancer is expected to occur in over 65,000 people in 2013, with over 13,000 deaths being attributed to the disease. The death rate is fairly steady annually, and most people don’t know they have it until it is in its advanced stage. “It’s a sneaky disease,” says Rathmell, “about one-third of tumors will reoccur after patients undergo resection.”

To treat the disease, the mainstay of available therapies is tyrosine kinase inhibitors (TKIs) that target the VEGF receptor. “Chemo doesn’t really work,” says Rathmell, “because the disease is very vascular. TKI drugs, [such as tivozanib and sorafanib], target the vasculature; not really the cancer cells.”

Targeting the VEGF receptor is just one corner of the market. “Standard of care used to be interferon even though it was never FDA approved,” says Rathwell. “It’s toxic, hard to give, and only works for a very small margin of patients. With the TKIs most people can take them and get some kind of response.”

In the TKI era, Rathmell assures, the survival time per patient is increasing. “Patients are living longer by a good margin than they were in the interferon era; and collectively, this can’t be pointed to just one drug in the renal cell armamentarium of drugs targeting cancers.”

Every drug opens up a new therapy choice for some patients. If approved, tivozanib will provide another option for patients with RCC as there’s always a patient that can match up better with a new drug than an already existing drug. “The goal is to achieve a long term of disease control without completely destroying quality of life,” says Rathmell.

Is PFS a clinically meaningful endpoint in cancer clinical trials, especially when crossover is part of the study design? Stay tuned - it will probably be a nail biter. First we'll see the FDA's review of the file and then we have ODAC on May 2nd.

By John McCleery, Managing Editor, OBR

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