The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 11-0 (1 abstention) in support of carfilzomib (Kyprolis, Onyx) as a new treatment option for patients with multiple myeloma, despite concerns raised by the FDA that a series of potentially lethal side effects could outweigh the benefits of the drug.
“Today’s ODAC recommendation is an important regulatory milestone in the review of Kyprolis for relapsed and refractory multiple myeloma,” said Ted W. Love, MD, Executive Vice President, Research and Development and Technical Operations, at Onyx Pharmaceuticals, in a statement issued on June 20, 2012. “Onyx is committed to bringing Kyprolis to patients as quickly as possible and looks forward to working closely with the FDA as the agency completes its review.”
The decision was primarily based on the results of PX-171-003, a phase II trial that enrolled 266 patients with relapsed or refractory multiple myeloma who had received at least two prior lines of therapy. In the trial, patients were given 20 mg/m2
of carfilzomib by intravenous bolus in the first cycle and 27 mg/m2
in each subsequent cycle. As a precaution, dexamethasone was administered with the first two cycles to alleviate a number of side effects observed, including fever, chills, shortness of breath, and vomiting, among others. If needed, investigators were allowed to continue treatment with dexamethasone in subsequent cycles.
The trial’s primary endpoint of overall response rate (ORR) was observed in 61 of the 266 enrolled patients (22.9%; 95% CI, 18%-28.5%) with duration of response lasting 7.8 months (95% CI, 6.5-9.7). However, according to the FDA’s own analysis the duration of response was only 6.5 months (95% CI, 4.6-8.3).
Prior to the ODAC vote, the FDA raised numerous concerns regarding side effects observed in the PX-171-003 trial and other earlier studies of carfilzomib. Among the most serious concerns were the cardiac and pulmonary toxicities seen in pre-clinical toxicity studies and hepatic impairment, which was responsible for two life-threatening cases of hepatic failure. Additionally, the FDA expressed concerns over the use of dexamethasone and whether the observed 22% ORR was enough to warrant approval.
However, despite these concerns, ODAC voted almost unanimously in favor of recommending the drug.
The FDA will decide whether to approve carfilzomib by July 27, 2012. While not required to follow ODAC’s advice, the FDA tends to uphold recommendations made by the panel. If approved, carfilzomib would be the eighth approved treatment for multiple myeloma.