SILVER SPRING, Md. -- An FDA advisory committee voted 11-0 with one abstention to recommend approval carfilzomib (Kyprolis) for patients with treatment-refractory multiple myeloma.
Members of the Oncologic Drugs Advisory Committee decided that the drug's promised benefits -- control of progressive disease in patients who have exhausted all other treatments -- outweighed the considerable risks.
"We need to put this in the context of patients who are really running out of options," said one panel member prior to the vote.
Other members who voted in favor said they were nervous about the risk-benefit balance, but were persuaded to support approval because of the need for new myeloma treatments.
The proposed indication would restrict the drug to patients relapsing or not responding after treatment with at least two other previous therapies, including a proteasome inhibitor and an immunomodulator.
The FDA has designated carfilzomib as eligible for accelerated approval, meaning that it would be approved on the basis of limited data but require the manufacturer to conduct confirmatory studies.
Carfilzomib, made by Onyx Pharmaceuticals, is a second-generation proteasome inhibitor, making it similar in action to the currently approved drug bortezomib (Velcade). Data from preclinical and human studies have indicated that the drug is active against bortezomib-resistant multiple myeloma cells.
It also appears that carfilzomib does not cause peripheral neuropathy, a major treatment-limiting side effect of bortezomib.
But in a briefing document prepared for the advisory committee, FDA staff had indicated that the drug's other toxicities may overwhelm its relatively modest efficacy.
Among 266 patients enrolled in the principal efficacy study, 24 died during the trial, half from causes other than disease progression.
The FDA review determined that nine of the deaths were clearly or potentially related to cardiac toxicity, with two others caused by liver failure and one by intracranial hemorrhage.
Moreover, about one-third of the 526 patients receiving carfilzomib in phase II trials discontinued because of adverse events.
"FDA is very concerned with the severe toxicities, including deaths that are associated with the use of this agent. The pathogenesis of these toxicities is not understood," the staff review concluded.
Much of the safety data came from single-arm studies, the FDA reviewers noted, making it difficult to determine whether an adverse effect resulted from the drug.
However, the incidence of cardiac, liver, and pulmonary effects was higher "than would be expected in this population of patients with multiple myeloma," and therefore must be attributed to carfilzomib, the review indicated. Many of the serious events occurred within 24 hours of administration, suggesting that they were infusion reactions.
Unusually for an oncology drug, the FDA agreed to accept the overall response rate (the sum of complete and partial responses) in an uncontrolled study as the primary efficacy endpoint, rather than survival-based measures in a randomized trial.
The overall response rate in the principal study was 22.9%, almost entirely consisting of partial responses. Median duration of response was about 7 months.
Phase III trials are underway, including a 780-patient-controlled study called ASPIRE that is evaluating carfilzomib in patients with relapsed but not necessarily refractory multiple myeloma. Results are slated to be available in 2014.
Representatives of Onyx pleaded with the committee not to recommend delaying approval until the ongoing trials are finished, citing the thousands of patients who would have to wait another two to three years before having access to the drug.
Patients and their advocates also called on the panel to vote for approval. Robin Tuohy, who serves as director of support groups for the International Myeloma Foundation and whose husband Michael has the disease, said patients were desperate for additional treatment options.
Michael Tuohy also spoke at the meeting. "Each new approval extends our lives," he told the committee. "Side effects don't scare me. I can deal with them. ... The alternative is death."
The FDA usually follows recommendations of its advisory committees but it is not required to do so.