DLBCL,   MCL,  FL

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
References
  1. Salles G. et al. Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. pii: S2152-2650(18)31284-9. DOI: 10.1016/j.clml.2018.12.013 [Epub ahead of print].
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