Daratumumab in R/R MCL, DLBCL and FL: Results of a phase II trial

Professor Gilles Salles from Lyon University, Lyon, FR and colleagues, recently published in the Clinical Lymphoma, Myeloma & Leukemia the results of a phase II trial that investigated the efficacy and safety of daratumumab monotherapy in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients.

Daratumumab is a CD38 monoclonal antibody, which has been approved for the treatment of newly-diagnosed multiple myeloma and has shown promising activity in pre-clinical NHL models. The aim of this global, proof-of-concept, phase II trial (NCT02413489) was to investigate whether single-agent daratumumab is efficient and safe for R/R mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) patients. The primary endpoint of the trial was overall response rate (ORR). Secondary endpoints, included safety and pharmacokinetics.

Study design & baseline characteristics

• N = 36 R/R NHL patients:
  • DLBCL: n = 15 patients
  • FL: n = 16 patients
  • MCL: n = 5 patients
• Median patient age (range): 64 (43–82) years
• Median time since diagnosis: 37.9 months
• Median number of prior treatment lines across all patients (range): 3 (2–10)
• All FL patients were previously-treated with rituximab and all MCL patients with ibrutinib
• Overall median CD38 expression across enrolled patients: 70%
  • DLBCL: 80%
  • FL: 67.5%
  • MCL: 60%
• Dosing:
  • Daratumumab (28-day cycles): 16 mg/kg by intravenous (IV) infusion once every week for eight weeks; then, every other week for 16 weeks; thereafter, every four weeks until disease progression (PD), unacceptable toxicity or study end
  • Pre-infusion medications:
    • Methylprednisolone: 100 mg IV, one hour prior to daratumumab for the first two infusions and 60 mg IV thereafter
      • Oral methylprednisolone of 20 mg was administered two days after the first three daratumumab infusions
    • Acetaminophen: 650–1000 mg one hour prior to daratumumab
    • Diphenhydramine: 25–50 mg IV one hour prior to daratumumab
  • Median number of daratumumab infusions (range):
    • DLBCL: 5 (2–24)
    • FL: 9 (2–30)
    • MCL: 5 (2–8)
  • Median number of daratumumab treatment cycles (range):
    • DLBCL: 2 (1–14)
    • FL: 3 (1–20)
    • MCL: 2 (1–2)
  • Median duration of daratumumab treatment (range):
    • DLBCL: 35 (8–366) days
    • FL: 70 (8–530) days
    • MCL: 36 (8–50) days 

Key results

• ORR per NHL patient cohort:
  • DLBCL: 6.7% (95% CI, 0.2–31.9)
  • FL: 12.5% (95% CI, 1.6–38.3)
  • MCL: no patients responded to treatment
• Among responders:
  • Time to response was:
    • DLBCL: 1.9 months (n = 1 responder)
    • FL: 2.3 months and 1.9 months (n = 2 responders)
  • Duration of response was:
    • DLBCL: 1.6 months
    • FL: 0.7 months and 7.4 months
  • Most DLBCL patients (73.3%) and MCL patients (80.0%) had PD
  • Most FL patients (62.5%) had stable disease (SD)
  • Clinical benefit rate (complete response + partial response + SD) was:
    • DLBCL: 13.3% (95% CI, 1.7–40.5)
    • FL: 75.0% (95% CI, 47.6–92.7)
    • MCL: 0%
  • Median progression-free survival (PFS) after a median follow-up (FU), was:
    • DLBCL (FU, 14.7 months): 1.2 months (95% CI, 0.6–1.7)
    • FL (FU, 11.5 months): 3.3 months (95% CI, 1.9–3.8)
    • MCL (FU, 15.4 months): 1.3 months (95% CI, 0.5–1.9)
  • Median overall survival (OS) after a median follow-up (FU), was:
    • DLBCL (FU, 14.7 months): 4.9 months (95% CI, 2.1–9.0)
    • FL (FU, 11.5 months): 17.2 months (95% CI, 15.0–not estimable)
    • MCL (FU, 15.4 months): 4.8 months (95% CI, 1.7–not estimable)

Safety

• All patients developed at least one treatment-emergent adverse event (TEAE)
• The most common TEAEs were:
  • Cough
  • Abdominal pain
  • Nausea
  • Fatigue
  • Pyrexia
• Grade 3−4 TEAEs occurred in:
  • DLBCL: 46.7% of patients
  • FL: 62.5% of patients
  • MCL: 60.0% of patients
• The most frequently reported Grade 3−4 TEAEs were:
  • Thrombocytopenia
  • Neutropenia
  • Hypertension
• Nine patients had Grade 3−4 TEAEs that were associated with daratumumab treatment
• Serious TEAEs occurred:
  • DLBCL: 40.0% of patients
  • FL: 37.5% of patients
  • MCL: 60.0% of patients
• Infusion-related reactions occurred in 72.2% of patients across all cohorts, with the most common one being cough:
  • DLBCL: 26.7%
  • FL: 25.0%
  • MCL: 80.0%
• Treatment discontinuation occurred in four patients due to TEAEs

Conclusions

• The response rates to daratumumab monotherapy were very low and its activity not promising in R/R MCL, FL and DLBCL patients 
• An unmet need for effective therapies against R/R NHL still exists