Carfilzomib Doubles PFS Over Bortezomib in Phase III Multiple Myeloma Trial

Carfilzomib (Kyprolis) doubled progression-free survival (PFS) versus bortezomib (Velcade) in patients with relapsed multiple myeloma in the phase III ENDEAVOR trial. The results were announced by the developer of carfilzomib, 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 carfilzomib or bortezomib. At a planned interim analysis, the trial met its primary endpoint with a significant improvement in PFS with carfilzomib: 18.7 versus 9.4 months.

“As new treatment options become available to patients with relapsed multiple myeloma, comparative trials, like ENDEAVOR, are becoming increasingly important to help physicians make informed decisions about the optimal care for patients," said Pablo J. Cagnoni, MD, president of Onyx.

Patients randomized to carfilzomib in the open-label, parallel assignment ENDEAVOR study received 20 mg/m² of the drug on days 1 and 2 of cycle 1, followed by 56 mg/m² on days 8, 9, 15, and 16. Those who tolerated the loading dose, continued to receive 56 mg/m² of carfilzomib on days 1, 2, 8, 9, 15, and 16 of 28-day cycles. The treatment was administered as a 30-minute infusion along with 20 mg of dexamethasone.

In the bortezomib arm, patients received 1.3 mg/m² of the drug in combination with 20 mg of dexamethasone. Bortezomib was administered in accordance with its label by physician’s choice of intravenous or subcutaneous injection. Subcutaneous delivery was received by more than 75% of patients.

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

Treatment with carfilzomib reduced the risk of disease progression by 47% versus bortezomib (95% CI, 0.44-0.65). Results were also superior with carfilzomib for the secondary outcome measures of overall response rate (ORR) and lower incidence of neuropathy. Data for overall survival (OS) have not yet matured.

"Demonstrating superiority over Velcade in this head-to-head trial supports our goal of ensuring continued improvement of patient outcomes and potentially establishing Kyprolis as the backbone of therapy for patients with multiple myeloma," said Cagnoni.

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 carfilzomib arm versus the bortezomib arm. These rates were comparable to those reported in the pivotal phase III ASPIRE study, which examined carfilzomib, lenalidomide, and low-dose dexamethasone versus lenalidomide, and low-dose dexamethasone alone in 792 patients with relapsed multiple myeloma.

The frequency of dyspnea and hypertension in the carfilzomib versus the bortezomib 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.

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.

Earlier this year, Amgen and its subsidiary Onyx, submitted a supplemental New Drug Application to the FDA for the full regulatory approval of carfilzomib 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. A. Keith Stewart, MBChB, from the Mayo Clinic in Scottsdale, Arizona, presented full data from the trial at the 2014 ASH Annual Meeting in December.

ASPIRE 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 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 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 ORR 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 ≥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 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%.

“We are excited about the results with Kyprolis in the ENDEAVOR and ASPIRE studies and the potential positive impact for patients with relapsed multiple myeloma,” said Robert A. Bradway, chairman and chief executive officer at Amgen, in a statement.

ENDEAVOR is the first of two phase III trials comparing carfilzomib head-to-head with bortezomib 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).