Treatment with single-agent carfilzomib (Kyprolis) was unable to significantly extend overall survival (OS) compared with best supportive care in heavily pretreated patients with multiple myeloma, according to results from the phase III FOCUS trial.
In the open-label trial, 315 patients with relapsed and refractory multiple myeloma who had received a median of 5 prior therapies were treated with carfilzomib or low-dose dexamethasone plus optional cyclophosphamide. Intravenous carfilzomib was administered at the standard dose and schedule for the first 9 cycles. From cycle 10 forward, carfilzomib was administered at 27 mg/m2
on days 1, 2, 15, and 16.
At the analysis, OS was equivalent in each arm, with a hazard ratio of 0.975 (95% CI, 0.76-1.249). Treatment discontinuation due to adverse events was comparable between the two arms. Cardiac events with carfilzomib were consistent with previous reports; however, a higher rate of all-grade renal toxicity was observed than what was indicated in the label.
The most common severe adverse events with carfilzomib are pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%), according to the label that contains data from 526 patients. Altogether, serious adverse reactions were reported in 45% of patients.
Renal toxicity observed prior to the FOCUS trial included increase in blood creatinine (24%) and renal failure (9%), which were mostly grade 1/2. Grade 3 renal adverse events occurred in 6% of patients and grade 4 toxicity was apparent in 1%. Blood creatinine levels and acute renal failure resulted in treatment discontinuation in 1% of patients for each event. Concurrent sepsis and worsening renal function resulted in death for 1 patient.
Amgen and its subsidiary Onyx Pharmaceuticals announced the early results from the FOCUS trial in a statement. Secondary endpoints of the study included progression-free survival (PFS), overall response rate, and safety. A full analysis from the study is expected at an upcoming medical meeting.
Carfilzomib received an initial approval for the treatment of patients with multiple myeloma who had received at least two prior therapies in July 2012. The accelerated approval from the FDA was based on a single-arm clinical trial, with phase III clinical data required for a full approval.
"While it is unfortunate that the FOCUS study did not meet its primary endpoint of overall survival, we believe the results from the recent positive ASPIRE phase III clinical trial will be sufficient to support regulatory submissions around the world," Pablo J. Cagnoni, MD, president, Onyx Pharmaceuticals, Inc., said in a statement.
Positive top-line results from the phase III ASPIRE trial that explored carfilzomib in patients with relapsed multiple myeloma were announced by Amgen and Onyx in early August. At this analysis, a significant 8.7-month delay in progression was seen with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone compared to lenalidomide and dexamethasone alone.
The median PFS was 26.3 months in the carfilzomib arm compared with 17.6 months in the control arm (HR=0.69; P
<.0001). Data on OS were not yet mature at the time of the analysis. More information from the study is expected later this year at the 2014 ASH Annual Meeting.