A negative survival trend and design flaws in the lone pivotal trial for Aveo Pharmaceuticals Inc.’s tivozanib outweighed the statistically significant progression-free survival benefit seen with the renal cell carcinoma drug, an FDA advisory committee said May 2.

FDA’s Oncologic Drugs Advisory Committee voted 13-1 that Aveo failed to demonstrate a favorable benefit/risk evaluation for treatment of renal cell carcinoma in an adequate and well-controlled trial. The panel’s patient representative was the lone vote in favor of approval.

Panelists recommending against approval said another pivotal trial was needed because the sole Phase III trial suggested an unfavorable survival trend for tivozanib versus the active comparator, Onyx Pharmaceuticals Inc./Bayer HealthCare LLC’s Nexavar (sorafenib).

Several clinicians on the panel said they would not know how to explain to a patient that tivozanib could delay disease progression but also potentially could lead to an earlier death.

Panelists also cited issues with the study’s design and execution, including the geographic distribution of patients. In the pivotal trial, 88% of patients were enrolled in Central/Eastern Europe, where practice patterns and standard of care do not match with those in the U.S. For example, access to second-line targeted therapy generally is not available in those regions, unlike in the U.S.

In addition, committee members questioned the wisdom and ethics of Aveo’s decision to use a one-way crossover design, whereby by patients who experienced disease progression on sorafenib in the pivotal trial could be switched to tivozanib. Aveo has asserted that this design, coupled with the high percentage of subjects from Central/Eastern Europe, created an imbalance in use of second-line targeted therapies that likely caused tivozanib to look worse on overall survival than sorafenib, even though it met the PFS primary endpoint.

“I do not believe that the data show a favorable benefit to risk,” committee member James Liebmann, University of Massachusetts, said. “I do think that having another trial that is conducted in a more appropriate fashion is absolutely indicated. I think that there is obviously promise with this drug, but I don’t think this trial demonstrated it.”

“I’m concerned about the conduct of the study, about the ethics of allowing crossover on only one arm in countries where other active therapies are not readily available,” ODAC chairman Mikkael Sekeres, Cleveland Clinic, said.

Sekeres was among several clinicians on the panel who said they would not know how to explain to a patient that tivozanib could delay disease progression but also potentially could lead to an earlier death.

“Our job on ODAC is to think about populations, to think about safety and efficacy and how a drug would be used across the United States,” he said. “But each of us is also a practicing doctor, and I cannot picture how I would be able to sit and talk with patients about treating him or her with a drug, tivozanib, that would allow that person to live without progression longer but possibly to die faster than if I treated that person with another available renal cell carcinoma drug.”

The panel’s recommendation against approval, coupled with agency reviewers’ criticisms of the pivotal trial and deep concerns about the adverse survival trend, suggest tivozanib is headed for a “complete response” letter by its July 28 user fee date.

Survival Hypothesis Unproven

Aveo entered the advisory committee on the defensive, having to explain why tivozanib should be approved when the final analysis for overall survival, a secondary endpoint in the pivotal trial, suggested a 25% increased risk of death compared with sorafenib, a finding that did not reach the level of statistical significance.

The findings on overall survival appeared inconsistent with the statistically significant 20% improvement in PFS, the primary endpoint.

In briefing documents released ahead of the meeting, FDA raised concerns about the overall survival data and the generalizability of the study findings to the U.S. patient population, since only 16 patients in the 517-patient study were from the U.S. In a May 2012 pre-NDA meeting, FDA recommended that Aveo conduct a second adequately powered, randomized trial in a population comparable to that in the U.S., advice the company did not follow ([A#14130430002]).

Although FDA’s briefing documents suggested Aveo was in for a challenging committee meeting, the tone of those documents was tame compared to the critiques by FDA reviewers at the advisory committee meeting, who said a flawed trial design produced uninterpretable results.

Division of Oncology Products 1 Deputy Director Amna Ibrahim said that although seven drugs have been approved for metastatic renal cell cancer, “none of them had this concerning issue” of an adverse survival trend. “In fact, no approved oncology drug has raised this kind of concern for a detriment in survival in recent trials that served as a basis for … approval.”

“The inconsistent PFS and OS results and imbalance in post-study treatments make the trial’s results uninterpretable and inconclusive when making the risk/benefit assessment necessary for approval of a drug,” FDA’s Ibrahim said.

Ibrahim acknowledged Aveo’s view that an imbalance in subsequent therapies between treatment arms led to the adverse trend on overall survival, but she said the company cannot prove this theory through post hoc analyses.

“It is possible that tivozanib is an effective drug and the sequential use after sorafenib improved survival on the sorafenib arm,” Ibrahim said. “But there may be other reasons as well, as these include that sorafenib is superior to tivozanib in terms of overall survival, and the very real possibility that death from toxicity contributed to a worse survival on the tivozanib arm.”

“The inconsistent PFS and OS results and imbalance in post-study treatments make the trial’s results uninterpretable and inconclusive when making the risk/benefit assessment necessary for approval of a drug,” she said. “Our advice to sponsors is that in the future, trials conducted outside of U.S. should reflect U.S. standard of care both during the trial and in post-study treatments.”

Is There “Compelling Evidence”?

Aveo cited tivozanib’s safety profile as one of the compound’s strengths and a distinguishing feature from other tyrosine kinase inhibitors approved for renal cell carcinoma, pointing out that it was associated with fewer adverse events that require dose modification, such as hand-foot syndrome and diarrhea, in the pivotal study.

However, FDA medical officer Dawn Arrington said the safety profile was comparable to that of other drugs approved for metastatic renal cell carcinoma, with serious toxicities including hypertension, cardiac dysfunction, thromboembolism, hepatic dysfunction and pancreatitis that have caused deaths. Furthermore, overall survival is the most important safety endpoint, she said.

Office of Hematology and Oncology Products Director Richard Pazdur asked ODAC to consider whether, given the uncertainty on overall survival, there was compelling evidence that would warrant a favorable approval action.

“This potential 25% increased risk of death is a very significant issue, and it really sets a new precedent as far as an oncology approval if this would go forward,” Pazdur said. “We have to take a look at why we would accept this uncertainty. … Is there an overwhelming efficacy signal here that would say yes, just abandon the survival curves? We have a modest difference in progression-free survival, but almost an equally negative impact on overall survival …and obviously overall survival is a much more important clinical endpoint than progression-free survival.”

Although they voted against approval, several panelists said they were nevertheless struck by testimony during the open public comment period, during which six renal cell carcinoma patients described their positive treatment experiences and improved quality of life with tivozanib.

The public comment period “was a very moving session and it clearly emphasized the need for high quality data, and listening to all of you talk actually made me angry that we’re sitting here today discussing this trial because of its severe limitations,” said temporary voting member Lori Dodd, National Institute of Allergy and Infectious Diseases. “I think if this trial had been conducted in a better way in terms of the design specifically, we might not be here.”

Aveo’s Tivozanib Falls On Survival Data, Study Design Flaws

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