Sean E. Harper, MD
Carfilzomib (Kyprolis) has received a positive recommendation from the EMA's Committee for Medicinal Products for Human Use (CHMP) for use in combination with dexamethasone alone as a treatment for patients with multiple myeloma following at least 1 prior therapy, according to the developer of the proteasome inhibitor, Amgen.
The recommendation was based on the the phase III ENDEAVOR study, in which carfilzomib and dexamethasone reduced the risk of progression by 47% compared with bortezomib (Velcade) and dexamethasone in patients with relapsed multiple myeloma. The median progression-free survival (PFS) with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53; 95% CI, 0.44-0.65; P
The CHMP opinion suggests carfilzomib is likely to be approved for this indication when the European Commission issues its final decision. The EC previously approved carfilzomib for use in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma following ≥1 prior therapy.
"In the first ever comparative phase III head-to-head study of 2 proteasome inhibitors in relapsed multiple myeloma, Kyprolis in combination with dexamethasone nearly doubled progression-free survival compared to a current standard of care regimen," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "We are pleased that the CHMP has recognized these robust data with a positive opinion, and we look forward to ensuring approval of this extended indication of Kyprolis."
In the phase III ENDEAVOR study, 929 patients were randomized to receive carfilzomib as a 30-minute infusion along with dexamethasone (n = 464) or bortezomib and dexamethasone (n = 465). Carfilzomib 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 bortezomib at 1.3 mg/m2. The majority of patients received bortezomib subcutaneously (75%).
The median age of patients enrolled in the trial was 65 years. All but 7% of patients had ECOG PS of 0 or 1 (about 50% ECOG 0), and about 20% 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 carfilzomib was consistent across subgroups. The median OS was 24.3 months in the bortezomib arm but had not yet been reached in the carfilzomib arm (HR, 0.79; P
= .066). However, at the time of the primary analysis, survival data were not yet mature.
The ORR was 77% with carfilzomib versus 63% with bortezomib. The complete response rate with carfilzomib was 13% versus 6% with bortezomib. The rate of very good partial response or better with carfilzomib was 54% compared with 29% with bortezomib.
Grade 3 adverse events (AEs) occurred more frequently in the carfilzomib arm compared with bortezomib (73% vs 67%). Additionally, serious AEs were more common with carfilzomib (48% vs 36%). However, dose reductions associated with AEs were more frequent with bortezomib versus carfilzomib (48% vs 23%). Treatment discontinuation due to AEs and on-study deaths were comparable between the two arms.
Grade ≥3 hematologic adverse events 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 carfilzomib versus bortezomib. The most frequent non-hematologic grade ≥3 AEs were diarrhea, fatigue, dyspnea, pyrexia, constipation, and insomnia.
Peripheral neuropathy occurred in 5% of patients treated with bortezomib and 1.3% of those in the carfilzomib arm. The proportion of patients with grade ≥2 peripheral neuropathy was significantly higher with bortezomib (32% vs 6%; P
In addition to the United States and Europe, carfilzomib is currently approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, and Russia.
Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. J Clin Oncol. 2015;(suppl; abstr 8509).