Aveo Pharmaceuticals Inc. will face the challenge of convincing FDA’s Oncologic Drugs Advisory Committee that its oral tyrosine kinase inhibitor tivozanib warrants approval for advanced renal cell carcinoma despite an unfavorable survival trend in the pivotal study.

In a notice posted on Feb. 26, FDA announced that ODAC would review tivozanib (proposed trade name Tivopath) during the morning of May 2. During the committee’s afternoon session, it will discuss Delcath Systems Inc.’s drug/device combination product Melblez Kit (melphalan injection for use with the Delcath Hepatic Delivery System) for treatment of patients with unresectable ocular melanoma that is metastatic to the liver.

The negative survival trend is bound to make FDA reviewers and ODAC members uncomfortable, despite the progression-free survival advantage seen with tivozanib.

Aveo attributes the negative survival trend to the tivozanib pivotal trial’s crossover design and the extensive use of post-progression, anti-VEGF therapies in the comparator arm.

Despite the trial’s success on the primary endpoint of progression-free survival, the negative survival trend is bound to make FDA reviewers and ODAC members uncomfortable about the prospects of approving tivozanib. It also could further renew debate on the use of crossover designs in pivotal trials to support oncologic approvals.

PFS Benefit Demonstrated …

Tivozanib is described as a potent, selective and long half-life inhibitor of all three vascular endothelial growth factor receptors that is designed to optimize VEGF blockade while minimizing off-target toxicities.

Under a 2011 deal, Aveo and Astellas Pharma Inc. share the development and regulatory costs for tivozanib in the EU and North America, with Aveo leading commercialization in the latter Also see "Astellas Pays $125MM Up-Front To Share Rights To AVEO's Tivozanib" - Pink Sheet, 16 February, 2011..

Submitted in September, the NDA broadly seeks approval for treatment of advanced renal cell carcinoma, although the companies have their eye on the first-line setting. Seven other drugs currently are approved for treatment of advanced renal cell carcinoma.

In the pivotal trial, TIVO-1, more than 500 patients with advanced renal cell carcinoma were randomized to tivozanib or Onyx Pharmaceuticals Inc./Bayer HealthCare LLC’s Nexavar (sorafenib). Patients were allowed to have had up to one prior systemic therapy, but prior use of VEGF or mTOR therapies was prohibited.

The trial had a superiority design and the primary endpoint was progression-free survival. Patients in the sorafenib arm were allowed to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression. No crossover protocol was available for patients in the tivozanib arm.

Tivozanib demonstrated a statistically significant improvement in PFS compared to sorafenib, with an approximately 20% reduced risk of disease progression or death. Median PFS in the tivozanib arm was 11.9 months compared with 9.1 months in the sorafenib group.

Tivozanib’s efficacy was more pronounced in treatment-naïve patients, who accounted for 70% of the total study population. There was a median PFS benefit of 3.6 months in this population (12.7 months tivozanib vs. 9.1 months sorafenib). Aveo has said this group represents the “true first-line setting” in North America and Europe and the most significant market opportunity for tivozanib Also see "Aveo/Astellas’ Tivozanib Bests Nexavar, Barely, In Advanced Kidney Cancer" - Pink Sheet, 3 January, 2012..

… But Overall Survival Trending The Wrong Way

The main problem for Aveo is in the overall survival data, which the company reported on Feb. 12 and which was included in the NDA filing.

The final survival analysis, which was conducted after all patients in the study had been followed for at least two years after randomization, showed a median survival of 28.8 months for tivozanib versus 29.3 months for sorafenib. The results suggested a 25% increased risk of death with tivozanib compared to sorafenib, although this difference did not reach the level of statistical significance.

An earlier, interim analysis had also shown a trend toward better overall survival in the sorafenib group. In an August 2012 Securities and Exchange Commission filing, Aveo said FDA “has expressed concern regarding the overall survival trend in the TIVO-1 trial and has said that it will review these findings at the time of the NDA filing as well as during the review of the NDA.”

Overall survival remains the efficacy “gold standard” for oncology drugs even though studies are not necessarily powered for such outcomes. Many oncology trials use progression-free survival as a primary endpoint because it provides a quicker path to approval, and then subsequently look at overall survival. But when a PFS endpoint is taken as early evidence and patients are allowed to cross over, a trial that may have been designed to continue for survival may never reach that endpoint.

The Crossover Defense

Crossover design studies are used so that potentially effective therapy is not denied to patients whose disease progresses while they are on study. However, use of such therapies after progression can muddy the true picture of an investigational agent’s impact on survival.

In a Feb. 12 press release, Aveo said the one-sided crossover design “resulted in a substantial difference in the use of subsequent therapies. Of the patients who discontinued their initial therapy, 10% originally on the tivozanib arm received subsequent anti- VEGF therapy (36% received any subsequent therapy) while 70% of patients originally on the comparator arm received subsequent anti-VEGF therapy (74% received any subsequent therapy).”

Aveo’s CMO told investors there is “little doubt that the overall survival results will be a focal point of some of the discussions” at the ODAC meeting.

Aveo executives devoted a substantial amount of time to the overall survival data during the company’s 2012 year-end earnings call on Feb. 13. Chief Medical Officer William Slichenmyer said the median survival times reported for both arms are among the longest ever seen in an advanced renal cell carcinoma study.

He said the company believes that a high rate of utilization of tivozanib among patients who had progressed on sorafenib helps to explain the survival data.

“There are emerging data in RCC and other tumor types to suggest that continuing anti-VEGF therapy after initial progression may allow for continued inhibition of tumor growth,” Slichenmyer said. “We believe that the differential utilization of second-line therapy in the two arms of TIVO-1 is impacting the relative performance of the two arms in the overall survival endpoint.”

“The numerically longer overall survival in the control arm was associated with a higher rate of utilization of effective next-line agents predominantly tivozanib,” he said. “In those patients who received tivozanib as next-line treatment after sorafenib, the median PFS was 8.4 months” with a confirmed response rate of 13%.

During the call, the company said it had been informed that FDA would convene an advisory committee meeting to review the NDA. “I think there is little doubt that the overall survival results will be a focal point of some of the discussions,” Slichenmyer said.

Inlyta’s ODAC Experience

Aveo may take a few lessons from Pfizer Inc.’s advisory committee experience with its renal cell carcinoma drug Inlyta (axitinib) in making a strong case for tivozanib’s approval based on its adverse event profile.

Differences in the toxicity profiles of axitinib and sorafenib proved instrumental in garnering a unanimous ODAC vote for approval during a December 2011 review of Pfizer’s drug ([A#00111212017]). Axitinib was associated with more hypertension, dysphonia and hypothyroidism in the pivotal trial, while sorafenib was associated with greater incidence of hand-foot syndrome, rash and alopecia.

FDA approved Inlyta in January 2012 for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy Also see "Inlyta Approval Expands Pfizer Kidney Cancer Options, But With Unique Safety Profile" - Pink Sheet, 27 January, 2012..

Tivozanib’s toxicity profile appears to differ from that of sorafenib. Aveo has reported that the most common adverse events in TIVO-1 were hypertension with tivozanib and hand-foot syndrome with sorafenib. The rate of dose interruptions due to adverse events was 18% in the tivozanib group compared with 35% for sorafenib.

Aveo’s Tivozanib Will Face Challenging Survival Data At ODAC Review

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