FDA Panel Falls Short of Recommending Panobinostat

Larry Hand

November 06, 2014

A US Food and Drug Administration (FDA) advisory committee voted 5 to 2 today against recommending approval of panobinostat (Farydak, Novartis) as a treatment for patients with relapsing multiple myeloma (MM) in combination with bortezomib (Velcade, Millennium) and dexamethasone.

But, committee members encouraged the manufacturer to continue to research the drug because they think it may be beneficial, just not under the conditions in the new drug application.

The majority of the members of the Oncologic Drugs Advisory Committee felt that the risks for harm or death outweighed the potential benefit in the panobinostat/bortezomib/dexamethasone combination.

Panobinostat is a new class of drugs called cinnamic hydroxamic acid and has been shown to target several pathways critical to MM biology. It is an inhibitor of histone and nonhistone deacetylases.

Novartis submitted evidence from two phase 3 studies and one phase 2 study in its application for FDA marketing approval. According to Novartis, patients in the first phase 3 trial who received the panobinostat combination treatment had a 37% reduced risk for disease progression or death compared with patients who received placebo/bortezomib/dexamethasome treatment (P < .0001). Those patients also experienced a statistically significant increase in progression-free survival of 3.9 months. They showed a trend, but not a statistically significant, increase of overall survival.

"There is an urgent clinical need for a new drug class with a novel mechanism which acts synergistically with our current regimens and overcome resistance. With panobinostat, there is in my view, robust and consistent evidence of clinical benefit," said Paul G. Richardson, MD, a clinical investigator, the RJ Corman Professor of Medicine at Harvard Medical School, and a clinician at Dana-Farber Cancer Institute in Boston, Massachusetts.

"The side effects are generally manageable with supportive care, appropriate dose reduction, and schedule change," he added. "Panobinostat offers a new treatment option for patients with relapse and refractory disease who have received at least one line of therapy and extends most importantly to those who've received multiple treatments."

However …

The primary end point analysis shows an increase in progression-free survival (PFS) of 3.9 months, said Nicole Gormley, MD, an FDA clinical reviewer. "However, large amounts of missing and censored data limit our confidence in these results. Sensitivity analyses for PFS showed significant variation in the observed PFS difference and underscores the uncertainty of the efficacy results.

"Also significant was twice the incidence of death not due to disease progression and a high incidence of mild depression, hemorrhage, infection, and cardiac toxicity. The high amount of observed toxicity, treatment discontinuation, the number of modifications required, combined with unreliable efficacy results, make the risk/benefit assessment of panabinostat in combination with bortezomib and dexamethasone challenging," she said.

Wrong Combination?

Panel member Bruce J. Roth, MD, assistant professor of medicine at Washington University School of Medicine and one of the no votes, said, "It's not that I don't believe that there's some potential biologic activity, because I think there is, it's just maybe the wrong combination or the wrong dose."

"I almost voted yes and I hope the company continues to pursue it, because I think this is a drug that might have activity in this disease and could be effective in these patients, but not in this combination. It's a no vote but it's a yes for the drug," said panel member Tito Fojo, MD, senior investigator and director of the medical oncology fellowship program at the National Cancer Institute, in Bethesda, Maryland.

Bernard F. Cole, PhD, a statistician and professor at the University of Vermont, in Burlington, said he voted yes because, "To me it seemed to be sufficiently robust. It also appeared to have some possibility, at least in some patients, for an overall survival benefit."

Panel chair Deborah K. Armstrong, MD, professor of oncology at Johns Hopkins University School of Medicine, Baltimore, Maryland, who voted no, summed it up this way: "This was a very difficult decision for me. I think this is a drug that has some activity, but progression-free survival, particularly when there are issues of missing data, is a concern to me."

No panel members reported any relevant financial relationships.

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