Despite moving testimony from patients stressing the need for more options to treat advanced kidney cancer, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted 13-1 Thursday against the adequacy of AVEO Oncology Inc.'s single Phase III trial to support the approval of tivozanib.

In a bit of a free fall since the FDA's negative briefing documents were released Tuesday, the Cambridge, Mass.-based biotech (NASDAQ:AVEO) halted trading during the meeting. ODAC's vote translated into new lows once trading resumed Thursday afternoon. (See BioWorld Today, May 1, 2013.)

Having closed Wednesday at $5.26, AVEO opened after Thursday's meeting at an all-time low of $2.25, a 57 percent drop. As the afternoon wore on, it picked up a little bit of lost ground to close at $2.65.

ODAC attributed its vote to a flawed trial design that didn't answer the questions about tivozanib's potential. Not one "to let the perfect be the enemy of the good," David Steensma, an associate professor at Harvard Medical School, said all trials are flawed. But this one had too many flaws.

"This was not an adequate well-controlled trial. Hopefully, there will be an adequate trial that will show benefit," he said, acknowledging the touching, heartfelt stories of the patients who testified during the public hearing about how tivozanib had made a difference in their lives.

Lori Dodd, a statistician with the National Institute of Allergy and Infectious Diseases, agreed. Listening to the patients' testimony "actually made me angry that we're sitting here today discussing this trial because of its severe limitations," she said.

Other committee members noted the millions of dollars that went into the multisite, global trial that enrolled more than 500 patients, saying the money should have been spent on a better designed study.

In a call after the meeting, AVEO President and CEO Tuan Ha-Ngoc defended the trial AVEO conducted in partnership with Astellas Pharma Inc., of Tokyo, saying the study design was based on consultations with leading experts in the field. AVEO recognized going into the meeting that the confounding nature of the crossover design, requested by trial investigators, would be an issue, but the CEO said he was dismayed at the comments that were made.

"While we are disappointed with the outcome of the ODAC vote, we remain confident in the efficacy, safety and tolerability of tivozanib in RCC patients," he said, adding that AVEO will work closely with the FDA to address the issues raised by the panel ahead of the drug's July 28 PDUFA date.

AVEO's confidence in the drug was shared by RBC Capital Markets analyst Adnan Butt, who said he believes tivozanib "could be a differentiated agent that could demonstrate better efficacy than existing kidney cancer drugs." But after ODAC's vote, it's clear another Phase III study will be needed, he said.

Butt noted that tivozanib is in several trials, including the TAURUS study, which is comparing the AVEO drug with Sutent (sunitinib, Pfizer Inc.). While data from that study are expected in the first half of 2014, Butt noted that it's unlikely TAURUS will be sufficient to address the FDA's focus on another randomized Phase III study.

Patient Support

The lone ODAC vote in support of the adequacy of AVEO's completed Phase III trial came from patient representative Dan Lumley, whose vote was based on the tolerability of tivozanib. Although several other VEGF tyrosine kinase inhibitors have been approved for renal cell cancer (RCC), they may not work for everyone and they each have specific adverse events that may make them intolerable for some patients.

Chris Battle, one of the patients who testified during the public hearing, said he has tried eight drugs since being diagnosed with cancer in 2009. Tivozanib, the eighth drug, is the first one that worked for him. "I'm running out of options," he told the committee, as he asked it to keep an open mind and approve more options for patients like him.

Richard Pazdur, director of the FDA's Office of Hematology & Oncology Products, said the agency is aware that patients want new options, but it can't approve a drug because of "wild enthusiasm not based on data."

Since multiple drugs are available for RCC, the agency felt no urgency to approve another one based on a single, unblinded Phase III trial that it considered flawed with inconclusive data. While the data met the primary endpoint of an improvement in progression-free survival (PFS), they pointed toward a possible decrease in overall survival (OS), which was a secondary endpoint. (See BioWorld Today, Feb. 14, 2013.)

AVEO pointed out that OS in both arms of the trial was among the longest seen to date in a pivotal RCC trial and attributed sorafenib's superior OS showing to a trial design that included a one-arm crossover permitting patients on sorafenib to switch to tivozanib. But Pazdur characterized that explanation as "just a hypothesis."

Dodd added that "this is a textbook example of why we recommend against crossovers."

While other RCC drugs have been approved based on PFS, they have not shown a possible negative OS. Given the OS data, approving tivozanib with this one trial would set a new precedent, Pazdur said.

The FDA's Jonathan Jarow made it clear that the agency isn't "setting a new regulatory standard for this indication." PFS is still acceptable as a primary endpoint for RCC, but a study drug must not show an adverse trend in OS, he said.

The clinical implications of the OS rate would be difficult to discuss with patients, especially since there's no explanation for it, several committee members noted. ODAC Chairman Mikkael Sekeres, an assistant professor at the Cleveland Clinic Taussig Cancer Institute, said that as a clinician, he couldn't picture how he would discuss the drug with patients as he'd have to tell them that it might help them live longer without disease progression, but they could die faster.

The OS trend and crossover design weren't the only parts of the trial that the FDA and ODAC found troubling. Since 90 percent of the trial subjects were in Central and Eastern Europe, the FDA questioned whether the data were applicable to U.S. patients, due to differences in standard of care and access to other cancer drugs.

While giving AVEO credit for using an active comparator when most of the approved VEGF drugs were tested against placebo, some committee members questioned the use of sorafenib as the comparator since it is no longer the first-line choice in the U.S.