Ofatumumab monotherapy in naïve FL patients: Results from a phase II trial

On 5 February 2019, Cara Rosenbaum from the Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA and colleagues, published in the British Journal of Haematology an Alliance phase II trial (CALGB-50901) investigating the efficacy of ofatumumab in naïve follicular lymphoma (FL) patients.

In this randomized, phase II trial (NCT01190449), previously-untreated low-to-intermediate risk FL patients were randomized to any of two different doses of ofatumumab monotherapy. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody that has been approved for the treatment of chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The primary objective of this trial was overall response rate (ORR). Secondary endpoints included, progression-free survival (PFS), and safety. 

Study design & baseline characteristics 

• N = 51 naïve low-to-intermediate risk (FL International Prognostic Index; FLIPI score 0−2) FL patients (Grade 1, 2, or 3a), aged ≥ 18, with disease stage III-IV or bulky stage II (single mass ≥ 7 cm)
• Patients were randomized to four weekly doses to either:
  • Ofatumumab 500 mg (n = 15)
  • Ofatumumab 1000 mg (n = 36)
    • After that, the dosing was extended to every 8 weeks for four additional doses, for a total duration of nine months or until disease progression (PD) or unacceptable toxicity
    • Due to slower accrual only the 1000 mg arm was kept. Patients in the 500 mg arm kept receiving this dose for the remaining study
    • Prior to each treatment dose, diphenhydramine (50−100 mg), glucocorticoid (equivalent to 20 mg dexamethasone) and acetaminophen (650 mg) were administered to minimise infusion related reactions (IRRs)
• Final patient numbers included in analysis, per arm:
  • 500 mg ofatumumab arm: n = 15
  • 1000 mg ofatumumab arm: n = 32
• Median patient age (range): 60 (40−85)
• Sex: 55% male
• FL Grade:
  • Grade 1: 45% of patients
  • Grade 2: 41% of patients
  • Grade 3a: 14% of patients
• FLIPI score:
  • Low risk: 21% of patients
  • Intermediate/low risk: 75% of patients

Key findings 

• Patients completing treatment plan (eight doses):
  • Ofatumumab 500 mg: 80% (n =12)
    • In these three patients who discontinued treatment in this arm, the reasons were:
      • PD: n = 2 (13%)
      • Lack of response (without PD): n = 1
    • Ofatumumab 1000 mg: 75% (n = 27)
      • In these nine patients who discontinued treatment in this arm, the reasons were:
        • PD: n = 2 (6%)
        • Switching to alternative therapy: n= 1
        • Consent withdrawal: n = 1
        • No specific reason: n = 1
        • Due to adverse events (AEs): n = 4
      • Of the patients in the 1000 mg ofatumumab arm (n = 36):
        • ORR: 84% (95% CI, 67−95%)
        • Best achieved response by month 12:
          • Complete response (CR): 9% (n = 3)
          • Partial response (PR): 75% (n = 24)
          • Stable disease (SD): 9% (n = 3)
          • Two patients achieving PR subsequently reached CR at months 22 and 27, respectively
            • CR: 16% (n = 5)
          • Of the patients in the 500 mg ofatumumab arm (n = 15):
            • ORR: 60% (95% CI, 32−84%)
            • Best achieved response by month 12:
              • CR: 7% (n = 1)
              • PR: 53% (n = 8)
              • SD: 33% (n = 5)
              • One patient who achieved PR subsequently achieved CR at month 18
            • At the time of this analysis, PD patients per arm were:
              • Ofatumumab 500 mg arm: 69% (n = 22)
              • Ofatumumab 1000 mg arm: 80% (n = 12)
            • At median follow-up (range): 30.7 months (<1−55.4), in the 1000 mg ofatumumab arm:
              • Median PFS: 1.9 years (95% CI, 1.5−3.0)
              • One-year PFS: 90% (95% CI, 73−97%)
              • Two-year PFS: 48% (95% CI, 29−64%)
              • Median duration of response (range): 23.7 months (95% CI, 16.6−36.2)
            • At median follow-up (range): 30.7 months (< 1−55.4), in the 1000 mg ofatumumab arm:
              • Median PFS: 1.9 years (95% CI, 1.0−1.9)
              • One-year PFS: 80% (95% CI, 50−93%)
              • Two-year PFS: 22% (95% CI, 5−46%)
              • Median duration of response (range): 16.5 months (95% CI, 11.6−50.6) 

Safety

• All participating patients remain alive
• No Grade 4 AEs occurred in any of the patients
• Grade 3 AEs occurred at an incidence rate of < 10%
• Most common hematological Grade 1−2 AEs:
  • Ofatumumab 1000 mg arm:
    • Lymphopenia: 28%
    • Anemia: 17%
    • Neutropenia: 14%
  • Most common hematological Grade 2−3 AEs:
    • Ofatumumab 500 mg arm:
      • Lymphopenia: 13%
      • Leucocytosis: 7%
    • In either arm, non-hematological AEs were mainly IRRs. No Grade 4 IRRs were reported
    • Treatment discontinuation due to toxicity alone in the overall population was 6% (n = 3; all in the 1000 mg ofatumumab arm)
      • Grade 3 IRRs (n = 2)

Conclusions 

• Ofatumumab at 1000 mg is well tolerated by low-to-intermediate risk, previously-untreated FL patients and has a low toxicity profile
• Ofatumumab resulted in mainly PRs with an ORR of 84% when administered to naive FL patients
• Ofatumumab does not appear superior to rituximab or obinutuzumab