Kyprolis Doubles Progression-Free Survival Over Velcade in Multiple Myeloma Trial

Kyprolis (carfilzomib) doubled progression-free survival (PFS) versus Velcade (bortezomib) in patients with relapsed multiple myeloma in the phase 3 ENDEAVOR trial. The results were announced by the developer of Kyprolis, Amgen, and its subsidiary Onyx Pharmaceuticals, Inc.

The head-to-head ENDEAVOR study randomized 929 patients with relapsed multiple myeloma to low-dose dexamethasone plus Kyprolis or Velcade. At a planned interim analysis, the trial met its primary endpoint with a significant improvement in PFS with Kyprolis: 18.7 versus 9.4 months.

Enrolled patients were required to have received between one and three previous treatment regimens. The international trial was conducted at 235 locations.

Treatment with Kyprolis reduced the risk of disease progression by 47 percent versus Velcade. Results were also superior with Kyprolis for the secondary outcome measures of overall response rate (ORR) and lower incidence of neuropathy. Data for overall survival (OS) have not yet matured.

Adverse event (AE)—induced treatment discontinuations and on-study deaths were similar between the two treatment groups. The rates for cardiac and renal failure were higher in the Kyprolis arm versus the Velcade arm. These rates were comparable to those reported in the pivotal phase 3 ASPIRE study, which examined Kyprolis, Revlimid (lenalidomide) and low-dose dexamethasone versus Revlimid, and low-dose dexamethasone alone in 792 patients with relapsed multiple myeloma.

The frequency of dyspnea and hypertension in the Kyprolis versus the Velcade arm in ENDEAVOR increased compared with the incidents reported in ASPIRE.

Amgen intends to submit full data for ENDEAVOR for presentation at the 2015 ASCO Annual Meeting this summer.

The Food and Drug Administration (FDA) granted an accelerated approval to Kyprolis in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including Velcade 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 Kyprolis was 22.9 percent. As a condition of the approval, Onyx was required to submit a full analysis from the ASPIRE trial.

Earlier this year, a supplemental New Drug Application was submitted to the FDA for the full regulatory approval of Kyprolis as a treatment for patients with relapsed multiple myeloma based on the results from ASPIRE. Early results from the study were announced in August 2014. Keith Stewart, from the Mayo Clinic in Scottsdale, Ariz., presented full data from the trial at the 2014 annual meeting of the American Society for Hematology held in December.

ASPIRE found that the combination of Kyprolis, Revlimid and low-dose dexamethasone reduced the risk of progression by 31 percent compared with Revlimid and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The median PFS with Kyprolis was 26.3 months compared with 17.6 months without the proteasome inhibitor.

At the 24-month interim analysis, 73.3 percent of patients in the Kyprolis arm were alive versus 65 percent with the two-drug regimen. The median overall survival was not yet reached with a trend favoring the carfilzomib arm.

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

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

The most common severe hematologic adverse events with Kyprolis compared with the control arm were neutropenia, anemia and thrombocytopenia. The most common severe nonhematologic side effect was pneumonia.

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

ENDEAVOR is the first of two phase 3 trials comparing Kyprolis head-to-head with Velcade in multiple myeloma. Results are still anticipated for the CLARION study, in which the two drugs, in combination with melphalan and prednisone, are being compared in the frontline setting (NCT01818752).