Results from an overall survival (OS) analysis of the phase II head-to-head ENDEAVOR trial were recently published in The Lancet Oncology (2017; doi:10.1016/ S1470-2045(17)30578-8). Data showed that carfilzomib administered at 56 mg/m2 twice weekly and dexamethasone (Kd56) reduced the risk of death by 21 percent over bortezomib and dexamethasone (Vd), resulting in a 7.6 month OS benefit (median OS 47.6 months for Kd56 vs. 40.0 for Vd, HR=0.79; p=0.01). The OS benefit was consistent regardless of prior bortezomib therapy (HR=0.75 for no prior bortezomib; HR=0.84 for prior bortezomib). This Kd56 regimen is already approved in the U.S., European Union, and other countries based on the primary analysis of progression-free survival (PFS) in the ENDEAVOR study.
“These results showed KYPROLIS and dexamethasone significantly reduced the risk of death compared to bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma,” said study co-author and investigator Meletios A. Dimopoulos, MD, Professor of Clinical Therapeutics at the National and Kapodistrian University of Athens, School of Medicine. “These results support the use of carfilzomib and dexamethasone as a standard of care for multiple myeloma patients at first relapse.”
Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. Notably, rates of grade 2 or higher peripheral neuropathy, a frequent dose-limiting toxicity of bortezomib, were five-times lower in patients receiving Kd56 versus patients receiving Vd (7% vs. 35%, respectively). The most common adverse events (greater than or equal to 20%) in the carfilzomib arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia, and headache.
As previously published in The Lancet Oncology, patients treated with Kd56 also achieved PFS of 18.7 months compared to 9.4 months in those receiving Vd, meeting the primary endpoint of the study (HR=0.53; 95% CI: 0.44 - 0.65; p<0.0001).
The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kd56 versus Vd in patients whose multiple myeloma has relapsed after at least one, but not more than three, prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death.
Patients received treatment until progression with carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of 28-day treatment cycles, along with low-dose dexamethasone (20 mg). For Cycle 1 only, carfilzomib was administered at 20 mg/m2 on days 1 and 2, and if tolerated was escalated to 56 mg/m2 from day 8 Cycle 1 onwards. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were treated with bortezomib administered subcutaneously or intravenously at the discretion of the investigator and in accordance with regional regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide.