ASCO 2018 | Phase III ARROW study: once weekly carfilzomib plus dexamethasone in RRMM

For patients with relapsed and refractory multiple myeloma (RRMM) there is an increasing need for new treatment options. Following promising data from the ENDEAVOR trial, which compared carfilzomib (K) plus dexamethasone (d) with bortezomib plus dexamethasone, carfilzomib is now routinely used in combination with dexamethasone or lenalidomide/dexamethasone to treat RRMM patients. Administration of the regimen necessitates twice-weekly intravenous injections, requiring patients to make arduous trips to the clinic.

However, new data (from the pre-planned interim analysis of the randomized phase III ARROW study) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting by Maria Victoria Mateos, from the University of Salamanca, Salamanca, Spain, suggests that a once-weekly dosing regimen could be equally effective. The study was conducted in collaboration with Philippe Moreau from the University Hospital of Nantes, Nantes, France, and was published in The Lancet Oncology on 1 June 2018.

Study Design:

• Pts with 2–3 prior therapies and prior exposure to proteasome inhibitor (PI) and immunomodulatory drug (IMiD) were eligible
• Pts (N = 478) were randomized 1:1 to receive Kd either once- or twice-weekly in a 28 day (d) cycle at the following doses:
• Once-weekly (n = 240) = K (30-min IV) on d1, 8, and 15 of all cycles (20 mg/m²) on d1 [cycle 1]; 70 mg/m² thereafter)
• Twice-weekly (n = 238) = K (10-min IV) on d1, 2, 8, 9, 15, and 16 (20 mg/m²on d1 and d2 during cycle 1 and 27 mg/m² thereafter
• All pts received 40 mg dexamethasone on d1, 8, 15 of all cycles, and d22 (for cycles 1–9 only)
• Primary endpoint = progression-free survival (PFS); secondary endpoints = overall response rate (ORR), overall survival (OS), safety, and pharmacokinetics

Key Highlights:

• Data from the CHAMPION-1 study to assess once-weekly dosing of carfilzomib, established:
• MTD for carfilzomib to be 70 mg/m²
• ORR = 77%, median PFS = 12.6 months; Grade 3 AEs = 62% at MTD
• Based on this, the ARROW study was designed to compare once-weekly (70 mg/m²) vs twice-weekly (27 mg/m²)

Data is given as once- vs  twice- weekly dosing:

• Data cut-off = 15 June 2017; median follow-up = 12.6 vs 12 months
• Median PFS (months) = 11.2 (95% CI, 8.6-13.0)vs 7.6 (95% CI, 5.8-9.2); HR = 0.69 (95% CI, 0.54-0.88); (P = 0.0029)
• ORR = 62.9% (95% CI, 56.5-69.0)vs 40.8% (95% CI, 35.5-47.3);(P< 0.0001);
• Complete response (CR) or better = 7.1% vs 1.7% 
• Grade ≥3 adverse events (AEs) = 68% vs 62%
• Treatment-related grade 5 AEs = 5 pts (2.1%) vs 2 pts (0.9%)
• Grade ≥3 hypertension = 5.9% vs 5%; cardiac failure = 2.9% vs 4.3%
• Sub-group analysis showed HR in favour of once-weekly regimen:
  • 2 prior lines of therapy: HR = 0.608 (0.429_­­-0.861)
  • 3 prior lines of therapy: HR = 0.823 (0.591-1.146)
  • Refractory to lenalidomide: HR = 0.756 (0.578-0.990)
  • Not refractory to lenalidomide: HR = 0.545 (0.319-0.934)

In conclusion, once-weekly Kd administered at 70 mg/m² significantly improved PFS and ORR in comparison with twice-weekly dosing at Kd at 27 mg/m². The occurrence of AEs was comparable for both regimens, with no added complications in the once-weekly group. Given the greater efficacy and added convenience of the once-weekly regimen, this is likely to be adopted going forward, but it will be interesting to see whether the increased cost for 70 mg/m² per week versus 54 mg/m² per week (27mg/m² twice weekly) can be offset by the reduction in patient hospital visits.   

To listen to Maria Mateos speaking about this data from ASCO 2018, click here, and for the Spanish version, click here.