FDA approval is being sought for a once-weekly dosing option of carfilzomib for use in combination with dexamethasone as a treatment for patients with relapsed/refractory multiple myeloma. Amgen, the manufacturer of the proteasome inhibitor, announced the submission of a supplemental new drug application seeking this approval today.
David M. Reese, MD
David M. Reese, MD
FDA approval is being sought for a once-weekly dosing option of carfilzomib (Kyprolis) for use in combination with dexamethasone as a treatment for patients with relapsed/refractory multiple myeloma. Amgen, the manufacturer of the proteasome inhibitor, announced the submission of a supplemental new drug application (sNDA) seeking this approval today.
The application is based on results from the phase III ARROW study, in which carfilzomib administered once weekly at 70 mg/m2with dexamethasone resulted in a prolonged progression-free survival (PFS) compared with the standard twice-weekly schedule in patients with relapsed/refractory multiple myeloma.1,2
The findings showed a median PFS of 11.2 months (95% CI, 8.6-13.0) with once weekly carfilzomib and dexamethasone compared with 7.6 months (95% CI, 5.8-9.2) for the standard twice-weekly schedule of carfilzomib at 27 mg/m2with dexamethasone (HR, 0.69; 95% CI, 0.54-0.88;P= .0029). These data met the primary endpoint of PFS.
Overall response rate (ORR) in patients in the once-weekly arm was 62.9% (95% CI, 56.5-69.0) versus 40.8% (95% CI, 35.5-47.3) in the twice-weekly arm (P<.0001). Additionally, 7% of patients in the once-weekly arm achieved a complete response (CR) or better. This is compared with 2% of patients who achieved a CR in the twice-weekly arm. ORR was a secondary endpoint, in addition to overall survival, and safety and tolerability.
"I'm proud of our continued dedication to the Kyprolis clinical program, with a focus on generating additional data to reduce the dosing and administration burden on patients with relapsed or refractory multiple myeloma," David M. Reese, MD, executive vice president of Research and Development at Amgen, said in a statement.
"Data from the phase III ARROW study illustrates Kyprolis's potential to extend the time patients live without their disease progressing while also providing a more convenient once-weekly dosing option for this frequently relapsing and difficult-to-treat cancer. We look forward to working with the [FDA] to bring this more streamlined dosing regimen to patients," added Reese.
Relapsed/refractory myeloma is a difficult-to-treat population, as progression often occurs. With ARROW, investigators aimed to prove PFS would not be compromised with an altered dosing schedule.
The phase III study enrolled 478 patients who had received 2 or 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Patients were randomized to either the once-weekly (n = 238) or twice-weekly schedule (n = 235), and were stratified by the International Stage System.
The maximum tolerated dose of carfilzomib at 70 mg/m2when given in combination with dexamethasone was established in the phase I/II CHAMPION-1 study, which was the first study to explore the once-weekly schedule.
Investigators reported that the once-weekly regimen, in addition to having a superior PFS, was more convenient for patients. Patients in the once-weekly group received carfilzomib intravenously for 30 minutes (20 mg/m2on day 1 of cycle 1; 70 mg/m2on days 8 and 15 of cycle 1; and 70 mg/m2on days 1, 8, and 15 of subsequent cycles), while patients in the twice-weekly group received it intravenously for 10 minutes (20 mg/m2on days 1 and 2 of cycle 1; 27 mg/m2on days 8, 9, 15, and 16 of cycle 1; and 27 mg/m2on days 1, 2, 8, 9, 15, and 16 of subsequent cycles). Patients received 40 mg of dexamethasone on days 1, 8, and 15 of all days and also on day 22 during cycles 1-9 in both arms.
Safety was comparable in each arm, and there were no new standard safety risks in the once-weekly arm, noted investigators. Common adverse events (AEs) were anemia, pneumonia, diarrhea, and thrombocytopenia. Even though patients in the once-weekly group experienced a higher rate of grade ≥3 AEs (68%) than the twice-weekly group (62%), they had less grade ≥3 cardiac AEs (3% vs 4%, respectively).
There were 5 treatment-related deaths in the once-weekly group, and 2 in the twice-weekly group. Deaths in the once-weekly group were attributed to sepsis, acute lung injury, acute respiratory distress syndrome, and tumor lysis syndrome. In the twice-weekly group, deaths were attributed to plasma cell myeloma and congestive heart failure.
Carfilzomib is approved for use in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 lines of therapy. The proteasome inhibitor is also approved as a single agent for the treatment of patients with relapsed/refractory multiple myeloma who have received 1 or more lines of therapy.