FDA Priority Review Granted to Carfilzomib sNDA in Myeloma

Sean E. Harper, MD

A supplemental new drug application (sNDA) for the full approval of carfilzomib (Kyprolis) as a treatment for patients with relapsed multiple myeloma has been granted a priority review by the FDA, according to the developer of the drug, Amgen. The FDA will make its final decision on the application by July 26, 2015.

Under the priority review, the FDA will evaluate data from the phase III ASPIRE trial, in which carfilzomib, lenalidomide, and low-dose dexamethasone reduced the risk of disease progression by 31% compared with lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma.

“The FDA’s priority review designation for Kyprolis underscores the need for new treatment options for patients with relapsed multiple myeloma, and we look forward to working with regulatory authorities throughout the review process,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement.

Carfilzomib received an accelerated approval from the FDA in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including bortezomib (Velcade) and an immunomodulatory agent, based on the results of a single-arm trial. As a condition of the approval, Amgen was required to submit a full analysis from ASPIRE.

The open-label phase III ASPIRE study enrolled 792 patients at a median age of 64 years who had received a median of two prior treatment regimens. Patients were randomized 1:1 to receive the three-drug carfilzomib regimen or lenalidomide plus low-dose dexamethasone alone. In both groups of the trial, 66% of patients had received prior bortezomib and 20% had prior lenalidomide.

In both arms, lenalidomide was administered at 25 mg on days 1 to 21 and dexamethasone was administered at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Intravenous carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 during cycles 1 to 12. On day 1 and 2 of the first cycle, carfilzomib was administered at 20 mg/m² followed by 27 mg/m² thereafter. Treatment with carfilzomib was not administered on days 8 and 9 during cycles 13 to 18 and was not administered beyond 18 cycles. However, median treatment exposure in the carfilzomib arm was 22 cycles.

The median progression-free survival (PFS) with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR = 0.69; 95% CI, 0.57-0.83; P <.0001).

At the 24-month interim analysis, 73.3% of patients in the carfilzomib arm were alive versus 65% with the two-drug regimen. The median overall survival was not yet reached with a trend favoring the carfilzomib arm (HR = 0.79; 95% CI, 0.63-0.99; P = .018).

The objective response rate was 87.4% versus 66.9% and the median duration of response was 28.6 months compared with 21.2 months with and without carfilzomib, respectively. Of patients who responded, the complete response rate was 17.7% with carfilzomib versus 5.1% without and the very good partial response rate was 70.4% with carfilzomib versus 40.7% in the control arm.

“Achieving deep and durable responses for patients with relapsed multiple myeloma is critical toward extending the time they live without their disease progressing,” said Harper.

Treatment discontinuation due to an adverse event occurred in 15.2% of patients treated with carfilzomib compared with 17.4% with the two-drug regimen.

The most common grade ≥3 hematologic adverse events with carfilzomib compared with the control arm were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%). The most common grade ≥3 nonhematologic side effects were pneumonia (12.5% vs 10.5%), hypokalemia (9.4% vs 4.9%), and hypophosphatemia (8.4% vs 4.6%).

For the three-drug regimen versus the two-drug regimen, respectively, all-grade acute renal failure occurred in 8.4% of patients versus 7.2%, cardiac failure was seen in 6.4% of patients versus 4.1%, and ischemic heart disease was experienced by 5.9% of patients compared with 4.6%.

Beyond the ASPIRE study, positive phase III outcomes for carfilzomib in relapsed multiple myeloma have also been demonstrated in the phase III ENDEAVOR trial. In early March, Amgen announced ENDEAVOR results showing that carfilzomib doubled PFS versus bortezomib at 18.7 versus 9.4 months, respectively. Amgen intends to submit full data for ENDEAVOR for presentation at the 2015 ASCO Annual Meeting.

The sNDA for carfilzomib in relapsed multiple myeloma was submitted in late January. At the time, Pablo J. Cagnoni, MD, president of Onyx Pharmaceuticals, an Amgen subsidiary, stressed the importance of continuing to advance therapeutic options for this patient population.

“Multiple myeloma is an incurable blood cancer that often becomes resistant to treatment, underscoring the need for new therapeutic options that provide deep and durable responses to extend the time patients live without their disease progressing.”