The agent gained a priority review designation for use in combination with dexamethasone for patients with relapsed multiple myeloma following prior treatment with at least one therapy, based on findings from the phase 3 ENDEAVOR trial.
In mid-September, the FDA granted a priority review designation to Kyprolis (carfilzomib) in combination with dexamethasone for patients with relapsed multiple myeloma following prior treatment with at least one therapy, based on findings from the phase 3 ENDEAVOR trial.
In the study, Kyprolis and dexamethasone reduced the risk of progression by 47 percent compared with Velcade (bortezomib) and dexamethasone. The median progression-free survival (PFS) with Kyprolis was 18.7 versus 9.4 months with Velcade.1 Under the priority review program, the FDA will make a decision by January 22.
"Clinicians need a range of options and robust clinical data to make informed choices that can ideally extend the time patients live without their cancer progressing," Sean E. Harper, executive vice president of Research and Development at Amgen, the company developing the drug, said in a statement. "The acceptance of this submission is an important next step toward providing more options for patients with relapsed multiple myeloma and we look forward to working with the FDA over the coming months."
In the phase 3 study, 929 patients were randomized to receive Kyprolis as a 30-minute infusion along with dexamethasone (464 patients) or Velcade and dexamethasone (465 patients). Kyprolis was administered at a starting dose of 20 mg/m2 on days 1 and 2 of cycle 1. If tolerated, the dose was escalated to 56 mg/m2 on day 8 of cycle 1. After this point, the 56 mg/m2 dose was maintained on days 9, 15 and 16 and throughout subsequent cycles. In the control arm, patients received Velcade at 1.3 mg/m2. The majority of patients received Velcade subcutaneously (75 percent).
The median age of patients enrolled in the trial was 65 years. All but 7 percent of patients had ECOG performance status of 0 or 1 (about 50 percent ECOG 0), and about 20 percent of the patients had high-risk cytogenetic by fluorescence in situ hybridization. The primary endpoint was PFS, with overall survival (OS), objective response rate (ORR), duration of response and safety as secondary measures.
The advantage in PFS seen with Kyprolis was consistent across subgroups. The median OS was 24.3 months in the Velcade arm but had not yet been reached in the Kyprolis arm. However, at the time of the primary analysis, survival data were not yet mature.
The ORR was 77 percent with Kyprolis versus 29 percent with Velcade. The complete response rate with Kyprolis was 13 percent versus 6 percent with Velcade. The rate of very good partial response or better with Kyprolis was 54 percent compared with 29 percent with Velcade.
Grade 3 adverse events (AEs) occurred more frequently in the Kyprolis arm compared with Velcade (73 percent vs 67 percent). Additionally, serious AEs were more common with Kyprolis (48 percent vs 36 percent). However, dose reductions associated with AEs were more frequent with Velcade versus Kyprolis (48 percent vs 23 percent). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.
Hematologic AEs that were at least grade 3 occurred in a similar proportion of patients in both groups, including anemia, thrombocytopenia, neutropenia, upper respiratory infection and pneumonia. However, there was an increase in the incidence of hypertension and dyspnea with Kyprolis versus Velcade. The most frequent non-hematologic AEs that were at least grade 3 were diarrhea, fatigue, dyspnea, pyrexia, constipation and insomnia.
Peripheral neuropathy occurred in 5 percent of patients treated with Velcade and 1.3 percent of those in the Kyprolis arm. The proportion of patients with at least grade 2 peripheral neuropathy was significantly higher with Velcade (32 percent versus 6 percent).
“The combination of [Kyprolis] and dexamethasone was superior to [Velcade] and dexamethasone regardless of age or prior [Velcade] exposure and represents a new standard of care,” lead investigator Meletios A. Dimopoulos, chair of clinical therapeutics at the University of Athens in Greece, said when the data were presented. “Although patients treated with [Kyprolis] and dexamethasone remained on study treatment longer, treatment discontinuation due to adverse events and on-study deaths due to adverse events were comparable between groups.”
Kyprolis was initially granted an accelerated approval in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including Velcade and an immunomodulatory agent. In July 2015, the FDA transitioned this to a full approval and expanded the indication to included the treatment of patients with relapsed multiple myeloma who have received at least one to three prior lines of therapy, based on results from the phase 3 ASPIRE trial.2
In the pivotal ASPIRE trial, the combination of Kyprolis, lenalidomide, and low-dose dexamethasone reduced the risk of progression by 31 percent compared with lenalidomide 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.