Phase IIa trial results from anti-CD19 therapy for R/R NHL

In February 2018, Wojciech Jurczak, from the Department of Hematology, Jagiellonian University, Kraków, Poland, and colleagues, had the results of their study published online ahead of print, in the Annals of Oncology. The study was a two-stage phase IIa trial (NCT01685008) on the clinical activity of a humanized Fc-engineered CD19 antibody for the treatment of relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) patients.

CD19, a B-cell antigen, has attracted a lot of attention as a potential target in NHL, due to its homogeneous expression in NHLs like diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). In an earlier phase I trial (NCT01161511), anti-CD19 therapy (MOR208, formerly XmAb 5574) showed preliminary tolerability and efficacy in R/R CLL patients. Thus, the aim of this open-label, single-arm, multicenter, two-stage phase IIa trial was to further assess anti-tumor activity of single-agent humanized Fc-enhanced anti-CD19 monoclonal antibody (MOR208) in patients with R/R B-cell NHL. The primary endpoint was overall response rate (ORR), while duration of response (DoR), progression-free survival (PFS) and safety were considered as secondary outcome measures.

 Patient population & study design

• N = 92 R/R patients after at least one rituximab cycle with histologically confirmed DLBCL, FL, CLL, marginal zone lymphoma (MZL) or mantle cell lymphoma (MCL)
  • n = 35 DLBCL (38%)
  • n = 34 FL (37%)
  • n = 12 MCL (13%)
  • n = 11 other indolent NHL (iNHL; 12%) (9, MZL; 2, CLL)
• Rituximab refractory disease: 91% of all patients
• Two cycles of anti-CD19 (MOR208) 12 mg/kg (IV) over two hours on Days 1, 8, 15 and 22 (28-day cycles)
• Additional (3^rd) cycle after 8 weeks for patients with partial (PR) or complete response (CR) or stable disease
• Patients with PR or CR after 3^rd cycle continued to receive 12 mg/kg anti-CD19 (MOR208) until disease progression or unacceptable toxicity (frequency of administration at investigator’s discretion)
• Mandatory prophylactic premedication (for the first three infusions in cycle 1): antipyretics, histamine H1 receptor blockers and glucocorticosteroids (80–120 mg IV methylprednisolone)

Key findings

• Based on responses, only the DLBCL (n = 35) and FL (n = 34) cohorts progressed to treatment stage 2 (MCL cohort: no response; iNHL cohort: 3 responses)
• ORR rates (stage 2):
  • DLBCL cohort: 26% (2 CR, 7 PR)
  • FL cohort: 29% (3 CR, 7 PR)
• Median time to response:
  • DLBCL cohort: 2.0 months
  • FL cohort: 2.8 months
• Stable disease:
  • DLBCL cohort: 14%
  • FL cohort: 47%
• ORR in patients with rituximab refractory disease:
  • DLBCL cohort: 21%
  • FL cohort: 24%
  • iNHL: 20%
• Median DoR (range):
  • DLBCL cohort: 20.1 (1.1–26.5) months
  • FL cohort: not reached (2.6–26.6 months)
  • Responses lasting ≥ 12 months observed in 5 DLBCL, 2 FL and 2 iNHL patients
• Median DoR (range) for rituximab refractory disease responders (n = 10):
  • DLBCL cohort: 19.8 (13.2–26) months
  • FL cohort: 16.4 (10.6–26.6) months
• Median PFS at 21-months follow-up:
  • DLBCL cohort: 2.7 months (91% CI [2.1–15.4])
  • FL cohort: 8.8 months (91% CI [5.3–27.1])
  • iNHL cohort: not reached (91% CI [2.0–NA])
• PFS rate at 12-months follow-up:
  • DLBCL and FL cohorts: 39%
• PFS was similar in patients with rituximab refractory vs rituximab non-refractory tumors (HR: 0.87; 95% CI [0.47–1.60]; P = 0.67)
• Longer PFS in patients with a baseline peripheral natural killer (NK) cell count ≥ 100 cells/µl (n = 36) vs those below this threshold (HR: 0.17; 95% CI [0.06–0.45]; P = 0.0004)

Safety

• Most frequently occurring adverse events (AEs) of any grade:
  • 12% IRRs: (n = 11/92)
  • 12% neutropenia (n = 11/92)
  • 1% grade 4 IRR (dyspnea)
  • 9% grade 3-4 neutropenia
• Hematological grade ≥ 3 AEs were most frequently reported in the DLBCL cohort
• Most common non-hematological grade ≥ 3 AEs were dyspnea and pneumonia
• 4% experienced severe AEs (SAE)
• 3% discontinued treatment due to AEs
• No treatment-related deaths

This study demonstrated promising clinical activity and a tolerable safety profile for the anti-CD19 monoclonal antibody MOR208, in R/R B-cell NHL patients. The authors ruled out the possibility of corticosteroid pre-medication contributing to the long-term anti-tumor effect of MOR208, by administering corticosteroids only once or twice monthly, after the initial treatment cycles. They concluded that this initial signal-seeking trial, with a short treatment duration, demonstrated promising potential for the use of anti-CD19 for R/R NHL patients, and should be extended to a longer treatment study in future clinical investigations.