FDA Panel Says No to Tivozanib in Renal Cell Cancer

Neil Osterweil

May 02, 2013

Patients with advanced renal cell carcinoma (RCC) and the clinicians who treat them will have to wait longer for approval — if it ever comes — of the tyrosine kinase inhibitor (TKI) tivozanib, following an overwhelming rejection by an advisory panel of results from a single, unblinded phase 3 trial.

The Food and Drug Administration (FDA)'s Oncologic Drugs Advisory Committee (ODAC) voted 13 to 1 that the data Aveo Pharmaceuticals submitted to the FDA to support the company's New Drug Application for tivozanib were not sufficient to prove that the drug was similar to existing agents in both efficacy and safety.

Data from the randomized phase 3 trial showed that the primary endpoint of progression-free survival for patients with metastatic RCC was significantly greater with tivozanib, at a median of 11.9 months, compared with sorafenib (Nexavar, Onyx Pharmaceuticals), at a median of 9.1 months (hazard ratio [HR], 0.80; P = .04).

But the same trial also showed a nonsignificant trend toward worse overall survival among patients assigned to tivozanib after all patients had been followed for at least 2 years. There were 118 deaths among 260 patients in the tivozanib group (45%) compared with 101 of 257 patients in the sorafenib group (39%). The hazard ratio for death was 1.25 (P = .11). In each trial group, 21 patients withdrew consent, and 6 were lost to follow-up and were censored at the time of withdrawal or loss to follow-up.

Robert Motzer, MD, an attending physician at the Memorial Sloan-Kettering Cancer Center in New York City, the lead investigator on the phase 3 trial, said that overall survival data were difficult to interpret. As with other pivotal trials of TKIs for RCC, the overall survival data were confounded by crossover to a second-line therapy, he explained. On the other hand, the data on progression-free survival and the safety profile of the drug were convincing evidence of benefit, said Dr. Motzer.

"I believe it is of the utmost importance for tivozanib to be available as a treatment option for our RCC patients," he said.

Committee members were less sanguine about the results, however.

"Our job on ODAC is to think about populations and think about efficacy and safety and how a drug will be used across the United States," said committee chair Mikkael Sekeres, MD, MS, associate professor of medicine at the Cleveland Clinic Taussig Cancer Institute in Ohio.

"But each of us is also a practicing doctor, and I cannot picture how I would be able to sit and talk with a patient 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," he said.

Multiple Targets

Tivozanib is a potent TKI active against multiple receptor tyrosine kinase targets, including vascular endothelial growth factor receptors 1, 2, and 3.

Aveo hopes that the agent will join a field of approved agents that includes other TKIs — sorafenib, sunitinib (Sutent, Pfizer), pazopanib (Votrient, GlaxoSmithKline), and axitinib (Inlyta, Pfizer) — as well as temsirolimus (Torisel, Pfizer) and bevacizumab (Avastin, Roche/Genentech) plus interferon-α.

But 13 of the 14 ODAC panelists voted "no" to the question "Has the applicant demonstrated a favorable benefit-to-risk evaluation for the treatment of renal cell carcinoma in an adequate and well-controlled trial?"

Only 1 panel member, Dan Lumley, a patient representative from Kansas City, Missouri, voted to recommend approval, based on a favorable adverse effect profile of tivozanib compared with other TKIs already approved for treatment of advanced RCC.

Among the panel members' concerns, apart from the survival signal, were the trial design, which allowed for crossover of sorafenib-treated patients to tivozanib, but not vice versa, and the fact that 80% of patients in the trial were enrolled in central and eastern Europe, where clinical care and the patient population are different from those in the United States.

Panel member Michael Menefee, MD, assistant professor of hematology-oncology at the Mayo Clinic in Jacksonville, Florida, noted that RCC is the fourth most common cancer among African Americans, yet only 1 African American was enrolled in the trial.

"I'm concerned about the conduct of the study, about the ethics of allowing crossover in only 1 arm in countries where other active therapies are not readily available," Dr. Sekeres said, explaining his negative vote.

Tuan Ha-Ngoc, president and chief executive officer of AVEO, said in a press statement that "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."

"We are committed to the RCC patient community and will work closely with the FDA to address the issues discussed by the panel today as the Agency continues its ongoing review of the New Drug Application for tivozanib," he said.

Dr. Motzer is a consultant to Aveo and was compensated for his time and expenses.

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