Amgen Seeks Full Approval for Carfilzomib in Myeloma

Keith Stewart, MBChB

Keith Stewart, MBChB

Amgen and its subsidiary Onyx Pharmaceuticals have submitted a supplemental New Drug Application (sNDA) to the FDA for the full regulatory approval of carfilzomib (Kyprolis) as a treatment for patients with relapsed multiple myeloma.

The sNDA was based on data from the phase III ASPIRE trial, which found that the combination of carfilzomib, lenalidomide, and low-dose dexamethasone reduced the risk of progression by 31% compared with lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma. 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).

Early results from the study were announced in August 2014. Keith Stewart, MBChB, from the Mayo Clinic in Scottsdale, Arizona, presented full data from the trial at the 2014 ASH Annual Meeting in December.

"The study was overwhelmingly positive. Its primary endpoint was progression-free survival, and patients on the 3-drug cocktail had an 8.7-month longer progression-free survival than the control arm," Stewart said in an interview withTargeted Oncology. "This is an unprecedented 26.3-month progression-free survival in this disease."

The open-label phase III 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 3-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 1-21 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 1-12. On day 1 and 2 of the first cycle, carfilzomib was administered at 20 mg/m²followed by 27 mg/m²thereafter. Treatment with carfilzomib was not administered on days 8 and 9 during cycles 13-18 and was not administered beyond 18 cycles. However, median treatment exposure in the carfilzomib arm was 22 cycles.

At the 24-month interim analysis, 73.3% of patients in the carfilzomib arm were alive versus 65% with the 2-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.

Treatment discontinuation due to an adverse event occurred in 15.2% of patients treated with carfilzomib compared with 17.4% with the 2-drug regimen.

The most common grade &ge;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 &ge;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 3-drug regimen versus the 2-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%.

"In some other studies with carfilzomib there has been a suggestion of events related to the heart—swelling, shortness of breath, potentially even cardiac failure. It was somewhat speculative, however, because we did not have randomized studies," Stewart said. "In fact, we see very little change, or very little increase in any of those side effects when carfilzomib is added. They are slightly higher, but patients are on treatment longer. When you look at serious events higher than grade 3, there was a negligible change in the two arms of the trial."

The FDA granted an accelerated approval to carfilzomib in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including bortezomib and an immunomodulatory agent. This indication was based on data from a single-arm clinical trial that enrolled 266 patients with relapsed multiple myeloma who received at least two prior therapies. In this study, the ORR with carfilzomib was 22.9%. As a condition of the approval, Onyx was required to submit a full analysis from the ASPIRE trial.

"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," said Pablo J. Cagnoni, MD, president, Onyx Pharmaceuticals, in a press release. "The US and EU submissions support our goal of bringing Kyprolis to patients with relapsed multiple myeloma."

Stewart KA, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract: 79.