The ENDEAVOR trial to compare the efficacy of carfilzomib and dexamethasone with bortezomib and dexamethasone - for treatment of RRMM

In January 2016 Meletios Dimopoulos and Philippe Moreau published the findings from the ENDEAVOR phase III trial, to compare the efficacy of the proteasome inhibitor (PI) carfilzomib administered in combination with dexamethasone, with the standard regimen of bortezomib and dexamethasone, to treat patients with relapsed and refractory Multiple Myeloma (RRMM). This study was published in The Lancet Oncology, and built upon previously published phase Ib/II and phase II studies, which showed early promise for carfilzomib in comparison to bortezomib. This open-label, multi-center study included 929 patients with RRMM, recruited from 198 sites globally between June 2012 and June 2014, who had one to three previous treatments. Patients were randomly assigned to either the carfilzomib (464) or bortezomib (465) group. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS) and overall response (OR).

Treatment:

• Carfilzomib was administered by i.v. at 20 mg/m² on days 1 and 2 of cycle 1
• For the remaining cycles, carfilzomib was given at a dose of 56 mg/m² on days 1, 2, 8, 9, 15, and 16
• Dexamethasone was given at a dose of 20 mg either orally or by i.v., on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle
• Dosing was based on preliminary results from the 56 mg/m² cohort of a phase 1b/2 study, in which a higher proportion of patients responded than compared with the phase 2 single-agent study of carfilzomib (27 mg/m²)
• Bortezomib was administered at a dose of 1·3 mg/m² by intravenous bolus or subcutaneous injection (3–5 s) on days 1, 4, 8, and 11
• Dexamethasone was given to the carfilzomib group at the same dose, but on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle
• Intravenous hydration was administered to the carfilzomib group at the investigator’s discretion, but was not required in the bortezomib group
• Treatment continued until disease progression or unacceptable toxic effects

Key Findings:

• At the interim analysis (November 2014), 200 patients (43%) in the carfilzomib group and 105 patients (23%) in the bortezomib group were still receiving treatment
• In the ITT population, 414 events (disease progression or death) had occurred: carfilzomib = 171 events, bortezomib = 243 events
• Median follow-up for PFS:
  • carfilzomib = 11.9 months (IQR 9.3-16.1)
  • bortezomib = 11.1 months (IQR 8.2-14.3)
  • HR = 0.69; 95% CI, 0.57-0.83; P=0.0001
• Median PFS:
  • carfilzomib = 18.7 months (95% CI, 15.6 months to not estimable)
  • bortezomib = 9.4 months (95% CI, 8.4-10.4 months)
  • HR = 0.53; 95% CI, 0.44-0.65; P<0.0001
• PFS across all subgroups was similar to the overall population
• Proportion of patients with an objective response:
  • carfilzomib = 77% (95% CI, 73-81)
  • bortezomib = 63% (95% CI, 58-67)
  • odds ratio (OR) = 2.03, (95% CI, 1.52-2.72) P<0.0001
• Median duration of response:
  • carfilzomib = 21.3 months (95% CI, 21.3 to not estimable); bortezomib = 10.4 months (95% CI, 9.-13.8)
• Mean time to response:
  • carfilzomib = 1.1 months (IQR 1.0-2.0); bortezomib = 1.1 months (IQR 1.0-1.9)
• OS data were immature for the interim analysis but at the time of data cutoff, there were:             carfilzomib = 75 deaths, bortezomib = 88 deaths (HR = 0.79 (95% CI 0.58-1.08) P=0.13)
• Median follow-up for OS:
  • carfilzomib = 12.5 months (IQR 9.6-16.6)
  • bortezomib = 11.9 months (IQR 9.3-15.9)
• Median duration of treatment:
  • carfilzomib = 39.9 weeks (IQR 23.7-53.0)
  • bortezomib = 26.8 weeks (IQR 15.0-42.0)
• Adverse Effects (AEs):
  • AEs ≥ grade 3:
    • Anemia: carfilzomib = 14%; bortezomib = 10%
    • Hypertension: carfilzomib = 9%; bortezomib = 3%
    • Thrombocytopenia: carfilzomib = 9%; bortezomib = 3%
    • Pneumonia: carfilzomib = 7%; bortezomib = 8%
  • AEs ≥ grade 2 or higher peripheral neuropathy:
    • carfilzomib = 32% (95% CI, 27.7-36.3); bortezomib = 6% (95% CI, 3.9-8.2)
    • OR = 0.14 (95% CI, 0.09-0.21); P<0.0001
  • Serious AEs: carfilzomib = 48%; bortezomib = 36%
  • Patients discontinued treatment due to AEs (ITT population):                                                      carfilzomib = 57%; bortezomib = 75%
  • Most commonly reported AE in both groups was peripheral neuropathy, and this was also the most common AE leading to either dose reduction, or treatment discontinuation, in both groups
  • AEs leading to dose reductions: carfilzomib group = 23%, bortezomib group = 48%
  • Overall there were 43 deaths during treatment or within 30 days of the last dose: carfilzomib = 22 patients; bortezomib = 21 patients

This was the first phase III trial to compare two protease inhibitors head-to-head, and provided comparative efficacy data for carfilzomib and bortezomib treatment regimens. Carfilzomib was found to confer a longer PFS, when compared with bortezomib, as well as more durable responses. Therefore, the authors concluded that carfilzomib, in combination with dexamethasone, should be considered a valid treatment option for patients for which bortezomib and dexamethasone would have been considered. The results from this trial provided pivotal data leading to the approval of a carfilzomib plus dexamethasone combination, for the treatment of RRMM patients, by both the US FDA and the EMA.