Surprise rejection of panobinostat for approval by 5-2 margin at ODAC Hearing
Today's Oncologic Drugs Advisory Committee (ODAC) hearing convened in an optimistic fashion with many in the myeloma community expecting there would be a recommendation for approval of panobinostat, an HDAC inhibitor used in combination with Velcade and dexamethasone. Publicly available data indicated a 3.9 months progression-free survival (PFS) or remission duration benefit with the three-drug panobinostat combination in patients who had been treated with 1-3 prior therapies. Note was made of significant toxicities, including low blood platelet levels (56.7%), diarrhea (25.4%), and fatigue (24.6%). However, going into the hearing, it was felt that the benefits outweighed these types of toxicities. From the myeloma patient perspective, there was the hope that panobinostat--representing a new class of drugs, the HDAC inhibitors--would be added to the myeloma treatment armamentarium. IMF staff and team members were at the ODAC hearing to affirm the continued unmet need for new drugs to treat myeloma.
Unfortunately, the presentation by Barry Miller, FDA Senior Clinical Analyst, dashed these hopes and expectations rather quickly. Miller pointed out that "missing data" was the main reason the FDA staff asked for the ODAC review. A large amount of data was unavailable or "censored," often because patients withdrew from the trial. The question was "Why?" Did the patients withdraw for incidental reasons (minor problems, trial logistics, etc.) or major toxicities, or even unexpected on-trial deaths?
As pointed out by Dr. James E. Liebmann (ODAC panelist from University of Massachusetts Memorial Medical Center), there was a disparity in "on-treatment deaths" in the panobinostat arm of the trial. The uncertainties about "censoring" apparently had led to four separate estimates of the PFS duration: 3.9 months (the duration reported); but also 2.2. months; 3.7 months, and 1.9 months. The FDA's own analyses gave a PFS difference of 2.2. months (9.9 months versus 7.7 months): rather disappointing compared to the 3.9 months provided by Novartis and their IRC (Independent Review Committee). IRC member Dr. Paul Richardson was unable to explain the reasons for the censoring to the satisfaction of the ODAC reviewers. Dr. Richard Pazdur (Director of the FDA Office of Hematology and Oncology Products) himself raised the issue of censoring as an important concern.
Ultimately, Dr. Richard Pazdur summarized what appeared to be the prevailing opinion of the ODAC reviewers.
"PFS is not the question, there's clearly some benefit. ... The question is what is the magnitude of benefit and does it warrant the toxicity."
This perspective reflected the vote of 5-2 against a recommendation to the FDA to approve panobinostat. Dr. Liebmann also summarized the difficulties faced by the panel when confronted, as they were, by patient advocates (Robin Tuohy, Michael Tuohy and Diane Moran) including a woman who had benefitted for five years on panobinostat. He said, "First, this is a very difficult decision... this agent does have some activity ... and can be useful in this disease. But, "I think the toxicity outweighed the marginal benefit in PFS."
He went on to say that we should not give up on the drug or class of drugs, and certainly this is the case. Although it seems very unlikely that the FDA will go against the ODAC recommendation, it may still be possible that Novartis can answer the questions that were raised.
This is certainly a wake-up call for the myeloma community. What are the expectations for new drugs moving forward? Do we need to set the bar higher and try to achieve a much greater benefit, especially in the setting of important toxicities? My sense is that all involved will be recalibrating and setting their sights on longer remissions and lesser side effects - key needs for myeloma patients everywhere!
Stay tuned and we will keep you posted as many new drugs move forward in trials and hopefully give the benefits we all want to see.
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