FDA Approves Addition of Survival Data to Carfilzomib Myeloma Label

David M. Reese, MD

David M. Reese, MD

A supplemental new drug application (sNDA) adding overall survival data from the phase III ASPIRE trial to the label for carfilzomib (Kyprolis) has been approved by the FDA, according to Amgen, the manufacturer of the proteasome inhibitor.  Carfilzomib is approved for use in patients with relapsed or refractory multiple myeloma.

In results of the ASPIRE trial, the combination of carfilzomib, lenalidomide (Revlimid), and dexamethasone reduced the risk of death by 21% compared with lenalidomide and dexamethasone alone for patients with relapsed multiple myeloma following prior treatment with 1 to 3 regimens.

The median OS with the carfilzomib combination was 48.3 months versus 40.4 months with lenalidomide/dexamethasone alone (HR, 0.79, 95% CI, 0.67-0.95;P= .0091).¹The OS benefit seen at the final analysis was consistent even in those who received prior treatment with the proteasome inhibitor bortezomib (Velcade).

"The ASPIRE trial showed significant improvement in survival in patients with relapsed or refractory multiple myeloma who received Kyprolis as part of a triplet regimen. With this approval, the US Prescribing Information for Kyprolis now includes positive overall survival data from two phase III trials, underscoring the important role of proteasome inhibition in the treatment of multiple myeloma,” David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen, said in a statement.

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 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.

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 1-12. 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 to 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, which was published in theNew England Journal of Medicine, 73.3% of patients in the carfilzomib arm were alive versus 65% with the 2-drug regimen.²The 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.

In addition to the ASPIRE trial, carfilzomib also showed an improvement in OS in the phase III ENDEAVOR study. In January 2018, the FDA approved an sNDA adding OS data from the ENDEAVOR trial to the label for carfilzomib.

In ENDEAVOR, carfilzomib in combination with dexamethasone extended OS by 7.6 months compared with bortezomib and dexamethasone (47.6 vs 40 months; HR, 0.791; 95% CI, 0.648-0.964;P= .01) in patients with relapsed/refractory multiple myeloma.³The OS benefit was consistent for both patients who received previous bortezomib (HR, 0.75) and those who did not (HR, 0.84).

Three-year follow-up data from ENDEAVOR showed that carfilzomib plus dexamethasone reduced the risk of death by 24% versus bortezomib/dexamethasone, with a 9-month median OS benefit (47.8 vs 38.8 months; HR, 0.76; 95% CI, 0.63-0.92;P= .0017).

There were no new safety concerns with the longer follow-up. Slightly more patients in the carfilzomib group experienced grade 3 or higher adverse events (AEs; 81% vs 71%). Frequent (≥5%) grade ≥3 AEs that occurred more often in the carfilzomib group included anemia (16% vs 10% in the bortezomib arm), hypertension (15% vs 3%), dyspnea (6% vs 2%), and decreased lymphocyte count (6% vs 2%). Rates of pneumonia (9%) and thrombocytopenia (9%) were equal in both groups.

Twenty-seven patients (6%) in the carfilzomib arm experienced grade ≥3 cardiac failure versus 9 patients (2%) in the bortezomib group. Six percent of patients assigned to carfilzomib and 3% of those assigned to bortezomib experienced grade ≥3 acute renal failure.

Carfilzomib is currently approved 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 treatment is also approved as a monotherapy for relapsed/refractory myeloma patients who have received 1 or more lines of therapy.

References:

1. FDA Approves Addition Of Positive Overall Survival Data From Phase 3 ASPIRE Trial To KYPROLIS® (carfilzomib) Label. Amgen. https://bit.ly/2LFIJbA. Published June 11, 2018. Accessed June 12, 2018.
2. Stewart KA, Rajkumar VS, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma.N Engl J Med. 2015; 372:142-152.
3. Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial [published online August 23, 2017].Lancet Oncol. doi: 10.1016/ S1470-2045(17)30578-8..