Meletios Dimopoulos, MD
Carfilzomib (Kyprolis) plus dexamethasone improved overall survival (OS) by 21% versus dexamethasone plus bortezomib (Velcade) in patients with relapsed or refractory multiple myeloma, according to findings from the phase III ENDEAVOR trial announced by Amgen.
The median OS was 47.6 months in the carfilzomib arm versus 40.0 months in bortezomib arm (HR, 0.79; 95% CI, 0.65-0.96). The safety data were consistent with previously reported study outcomes. The full updated results from the trial will be presented at the 16th International Myeloma Workshop, which is being held in New Delhi from March 1 to 4, 2017.
"For an incurable disease like multiple myeloma, a major treatment goal for oncologists and hematologists is to help patients live as long as possible," study co-author and investigator Meletios A. Dimopoulos, MD, professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine said in a statement. "Based on these data, we now know that Kyprolis not only significantly extended progression-free survival (PFS)compared to Velcade, but also OS, making it a clinically meaningful advance in the treatment of relapsed or refractory multiple myeloma."
The phase III ENDEAVOR study randomized 929 patients 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 OS, objective response rate (ORR), duration of response, and safety as secondary measures.
Carfilzomib and dexamethasone reduced the risk of progression by 47% compared with bortezomib (Velcade) and dexamethasone. The median PFS with carfilzomib was 18.7 versus 9.4 months with bortezomib (HR, 0.53; 95% CI, 0.44-0.65; P <.0001). The advantage in PFS seen with carfilzomib was consistent across subgroups.
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% versus 6%; P <.0001).
Commenting on the ENDEAVOR update, Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said, “These results confirm the superiority of Kyprolis over Velcade in relapsed or refractory multiple myeloma patients," said "A survival benefit has rarely been demonstrated in relapsed or refractory multiple myeloma. Endeavor is the only study to demonstrate a survival benefit in a head-to-head comparison with a current standard of care regimen. These results further support Kyprolis as a foundational therapy in this patient population."