The MAVORIC phase III trial: vorinostat versus mogamulizumab for previously treated CTCL

Results from the MAVORIC (NCT01728805), the largest randomized clinical trial in cutaneous T-cell lymphoma (CTCL) to date, were published in The Lancet Oncology by Kim H. Youn from Stanford University, California, US, and colleagues. In this phase III trial, mogamulizumab was compared against vorinostat in previously treated CTCL patients.

Vorinostat is one of the current systemic regimens for the CTCL subtypes: mycosis fungoides (treatment-resistant early-stage or advanced stage), and Sézary syndrome that has been approved by the US Food and Drug Administration (FDA). In this international, open-label, randomized, phase III trial, the efficacy of vorinostat in relapsed or refractory (R/R) CTCL patients was compared to mogamulizumab, a first-class anti-CC chemokine receptor 4 (CCR4) monoclonal antibody. The primary outcome of the study was progression-free survival (PFS), while secondary outcomes included overall response rate (ORR), and duration of response (DoR).

Study overview

• N = 372 patients with R/R mycosis fungoides or Sézary syndrome were enrolled at 61 medical centres in the US, Denmark, France, Italy, Germany, the Netherlands, Spain, Switzerland, UK, Japan, and Australia
• Eligible patients:
  • Histologically confirmed R/R stage IB−IVB mycosis fungoides or Sézary syndrome (≥ 18−20 years)
  • Failed at least one previous systemic treatment
  • Eastern Cooperative Oncology Group performance (ECOG) status ≤ 1
• The intention-to-treat (ITT) population was comprised of patients randomly assigned 1:1 to mogamulizumab (n = 186) or vorinostat (n = 186) and stratified by CTCL subtype (mycosis fungoides vs Sézary syndrome) and disease stage (IB−II vs III−IV). Two patients in the mogamulizumab group withdrew consent leading to n = 370 patients in the safety population
• Both treatments were administered in an outpatient basis with each treatment cycle lasting for 28 days:
  • Mogamulizumab was administered at 1 mg/kg intravenously on Day 1, 8, 15 and 22 (once weekly) of the first cycle and on Day 1 and 15 (once bi-weekly) in subsequent cycles
  • Vorinostat was administered at 400 mg orally, once daily with food beginning from Day 1
  • Patients could continue treatment until disease progression, drug intolerance, unacceptable toxicity or if any other discontinuation criteria were met

Key findings

PFS

• At data cut off (December 31, 2016), mogamulizumab resulted in significantly higher median investigator-assessed PFS than vorinostat (7.7 months [95% CI, 5.7−3] vs 3.1 months [95% CI, 2.9−4.1]; P < 0.0001, HR = 0.53 [95% CI, 0.41−0.69])
• Mogamulizumab also resulted in superior median PFS when compared to vorinostat following an independent review (6.7 months [95% CI, 5.6−4) vs 3.8 months [95% CI, 3.0−4.7]; P < 0.0007, HR = 0.64 [95% CI, 0.49−0.84])
• Improved median PFS with mogamulizumab vs vorinostat was consistent across all four different PFS sensitivity analyses that the authors performed

ORR

• Investigator-assessed ORR was significantly higher for patients receiving mogamulizumab (28%) than those receiving vorinostat (5%; RR = 23.1 [95% CI, 12.8−1]; P < 0.0001]
• This was further confirmed by the independent review analysis (P < 0.0001)
• Five patients in the mogamulizumab group achieved a complete response (CR), as compared to zero patients in the vorinostat group
• A best overall global response was achieved by 35% of patients receiving mogamulizumab compared to 6% of vorinostat-receiving patients
• Of the 186 vorinostat patients, 136 (80%) crossed over to mogamulizumab therapy. From these patients, 31% (41) of them achieved an overall response
• No apparent differences were observed in the number of patients achieving an overall response on the basis of skin CCR4 expression analysis

DoR

• In the mogamulizumab group, the 52 patients who responded had a median blood DoR of 25.5 months (15.9−not estimable), skin DoR of 20.6 months (11.2−not estimable) and lymph node DoR of 15.5 months (15.5−15.5)
• In the vorinostat group, the 9 patients who responded had non-estimable blood and lymph node DoR and a skin DoR of 10.7 months (4.8−not estimable)

Safety

• The most common mogamulizumab-emergent adverse events (AEs) of any cause and grade in the safety population (n = 184) were:
  • Infusion-related reactions (34%)
  • Drug rash (24%)
  • Diarrhea (24%)
  • Fatigue (24%)
• Grade 3−4 AEs in the mogamulizumab group occurred in 41% (75/184) of patients, similar to the vorinostat group (41%, 76/186)
• The most commonly reported serious AEs (SAEs) in the mogamulizumab group (N = 184) were:
  • Pyrexia (4%)
  • Cellulitis (3%)
• The most commonly reported SAEs in the vorinostat group (n = 186) were:
  • Cellulitis (3%)
  • Pulmonary embolism (3%)
  • Sepsis (3%)
• Two out of three (67%) deaths in the mogamulizumab group were considered as treatment-related (sepsis and polymyositis), while three out of nine (33%) in the vorinostat group (two pulmonary embolisms and one bronchopneumonia)

The authors concluded that in patients with previously-treated mycosis fungoides or Sézary syndrome, mogamulizumab leads to significantly superior PFS and ORR than the current standard of care, vorinostat. Despite the higher efficacy of mogamulizumab, its safety profile was similar to vorinostat, further indicating its great potential as a novel therapy for R/R CTCL.