Carfilzomib, a second-generation proteasome inhibitor administered intravenously, has been approved to treat patients with refractory multiple myeloma, the Food and Drug Administration announced on July 20.
The indication specifies use in patients who have received at least two prior lines of therapy that included the first-generation proteasome inhibitor bortezomib (Velcade) and an immunomodulatory drug (IMiD), and who have evidence of disease progression on or within 60 days of completing the last therapy,
Bortezomib was approved in 2003, and is among the new agents credited with prolonging the lives of patients with multiple myeloma. Carfilzomib will be marketed as Kyprolis by Onyx Pharmaceuticals. In clinical trials, it was effective in patients who stopped responding to bortezomib and to IMiDs, and it also appeared to cause less peripheral neuropathy.
The prescribing information for carfilzomib states that approval was based on response rate, and that clinical benefit, such as improvement in survival or symptoms, "has not been verified."
Carfilzomib received an accelerated approval, based on clinical evidence that the treatment has an effect on a surrogate end point that is "reasonably likely to predict a clinical benefit to patients," according to the Food and Drug Administration. As a condition of accelerated approval, manufacturers are required to provide more clinical data confirming benefit, and if the follow-up studies fail to confirm benefit, the FDA can withdraw approval.
Onyx announced that it has completed enrollment in a phase III confirmatory study.
The accelerated approval was based on a phase IIb study of 266 patients with relapsed or refractory multiple myeloma, previously treated with at least two therapies, including bortezomib and an IMiD – thalidomide or lenalidomide (Revlimid). The patients started treatment with carfilzomib (administered twice weekly for 3 weeks, followed by a rest period, in a 28-day cycle) a median of 5.4 years after the initial diagnosis.
The overall response rate (complete responses, very good partial responses, and partial responses combined) was 23%, and the median duration of response was almost 8 months. Most responses were partial (18%), but one patient had a complete response.
The most commonly reported adverse effects associated with treatment were anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia, which were reported in 30% or more of patients in the study, according to the FDA. Serious adverse events were heart failure and shortness of breath.
At a meeting in June, the FDA’s Oncologic Drugs Advisory Committee supported accelerated approval of the drug for this population, noting that there are few if any treatment options available for patients with end-stage multiple myeloma, and that the response rate and safety profile observed in the phase II study were acceptable and justified an accelerated approval.
The confirmatory study, an international phase III study known as the ASPIRE study, is evaluating the combination of lenalidomide and low-dose dexamethasone with or without carfilzomib in patients with relapsed multiple myeloma who have received one to three previous therapies, according to the statement from Onyx announcing the approval.
Other studies that are underway include a phase III study evaluating carfilzomib as a single treatment for patients with relapsed and refractory myeloma who have received three or more prior therapies (FOCUS trial), which the company said is designed to "facilitate" approvals worldwide.
Another study, the ENDEAVOR trial, is comparing the combination of carfilzomib and low-dose dexamethasone to the combination of bortezomib and low-dose dexamethasone, according to Onyx.
The FDA statement cited American Cancer Society estimates that 21,700 people will be diagnosed with multiple myeloma and 10,710 will die from the disease in 2012.
"We are encouraged by the continued progress in the development of drugs for multiple myeloma over the past decade, offering improved treatment of this disease," Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release.
The Multiple Myeloma Research Foundation issued a statement commending the FDA and Onyx for making carfilzomib available to patients with multiple myeloma. The foundation and its affiliated clinical trials network, the Multiple Myeloma Research Consortium, had helped Onyx with the pivotal clinical trial.
Kathy Giusti, founder and chief executive officer of the groups, called the approval "an immensely important milestone for the multiple myeloma patient community, which continues to face significant unmet need in terms of safe and effective treatments for advanced disease. While we have seen tremendous progress in the past decade, multiple myeloma remains incurable," she said.
The carfilzomib prescribing information is available here.