Last week the US Food and Drug Administration (FDA) approved carfilzomib (Kyprolis), a novel, highly selective epoxyketone proteasome inhibitor that is administered intravenously, to treat patients with multiple myeloma who have received at least two prior therapies, including treatment with bortezomib (Velcade) and an immunomodulatory therapy.
The trial that led to the approval, PX-171-003, was an open-label, single-arm phase II trial that enrolled 266 patients with relapsed or refractory multiple myeloma. The patients in the trial were heavily pretreated, and had received at least two prior lines of therapy (median of five prior lines of therapy), including bortezomib, lenalidomide, and thalidomide (Thalomid). Carfilzomib was administered intravenously in doses of 20 mg/m2 twice weekly for 3 of 4 weeks in the first cycle, then 27 mg/m2 for up to twelve cycles.
The primary endpoint of the study was overall response rate; secondary endpoints included clinical benefit response rate, duration of response, progression-free survival, overall survival, and safety. The study found that 61 of 266 patients (22.9%) experienced complete or partial disappearance of their tumors with a median duration of response of 7.8 months (95% CI, 6.5-9.7). Median overall survival was 15.6 months.
The most common adverse events of the study participants were fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%). Peripheral neuropathy, primarily of grade 1 and 2, was experienced by 33 patients (12.4%). Serious side effects seen with carfilzomib included heart failure and shortness of breath. In all, 33 patients (12.4%) withdrew due to an adverse event. Patients should be monitored closely and treatment withheld if these serious side effects occur.
The American Cancer Society estimates that 21,700 people will be diagnosed with multiple myeloma and 10,710 will die from the disease this year.
“The approval of Kyprolis provides a treatment option to patients with multiple myeloma whose disease has progressed despite use of available therapies,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “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.”
The drug was approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. As part of this accelerated process, the manufacturer, Onyx Pharmaceuticals, will have to conduct additional studies that confirm these results.