Single-Agent MOR208 in Relapsed or Refractory (R-R) Non-Hodgkin's Lymphoma (NHL): Results from Diffuse Large B-Cell Lymphoma (DLBCL) and Indolent NHL Subgroups of a Phase IIa Study

Introduction: The B-lymphocyte, lineage specific surface antigen CD19 is broadly and homogeneously expressed in most B-cell non-Hodgkin's lymphomas (NHL). As a co-stimulatory molecule of the B-cell receptor complex it is an important regulator of transmembrane signals in B-cells. Phosphorylation of intracellular tyrosine residues of CD19 may augment signal transduction in multiple pro-survival and proliferation pathways ( e.g. PI3K and BTK). This makes CD19 an attractive target for the treatment of B-cell malignancies. MOR208 is a Fc-enhanced CD19 monoclonal antibody. The Fc-enhancement of MOR208 leads to a potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP). MOR208 also induces direct cytotoxicity, potentially by disrupting B-cell receptor (BCR) signalling. Thus MOR208 may have clinical use as a new therapeutic agent in patients with (R-R) B-cell malignancies.

Methods: This is an open-label, multicenter, phase IIa study of MOR208 in R-R NHL patients progressing after at least one prior rituximab-containing therapy. Patients were enrolled into 1 of 4 cohorts of aggressive and indolent (i) NHLs. Treatment comprised single-agent MOR208, 12 mg/kg IV, weekly, for 8 weeks (2 cycles), which could continue for 4 additional weeks in patients with at least stable disease (SD) after 2 cycles. Patients with complete responses (CRs) or partial responses (PRs) at 12 weeks could continue with bi-weekly or monthly MOR208 treatment until progression. The primary endpoint was the objective response rate (ORR), which was assessed by the investigator. Secondary endpoints included progression-free survival (PFS), duration of response (DoR) as well as incidence and severity of adverse events (AEs). This analysis includes the evaluation of potentially predictive and prognostic biomarkers in DLBCL and iNHL cohorts.

Results: In total, 92 patients were enrolled including 35 (38%) with DLBCL and 45 (49%) with iNHL. Median age was 71 years in the DLBCL cohort and 66 years in the iNHL cohort. 30 (86%) DLBCL patients and 40 (89%) iNHL patients had stage III-IV disease; 12 (34%) and 21 (47%) had received ≥3 prior lines of therapy, respectively. In the DLBCL cohort 24 (69%) patients were rituximab refractory as were 22 (49%) patients in the iNHL cohort. ORR was 26%, including 2 CRs and 7 PRs in the DLBCL cohort, and 29% including 5 CRs and 8 PRs in the iNHL cohort; 5/9 and 5/13 responders were rituximab refractory, respectively. The disease control rate (DCR, CR+PR+SD) was 40% in the DLBCL and 73% in the iNHL cohorts. Reduction in target lesion size was also seen in 5/6 DLBCL and 12/16 iNHL patients with SD (central assessment). Median DoR was 20 months for DLBCL patients (95% CI 11.3-not available; 3 ongoing) and not reached for iNHL (6 ongoing), with the longest duration of response lasting >26 months in both cohorts. In patients with rituximab non-refractory and refractory tumors the 12-month PFS rate was 40% in both the DLBCL and iNHL cohorts. DCR (65% vs 54%; p=0.35) and PFS (median 6.6 vs 5.3 months, hazard ratio [HR] 0.85, 95% CI 0.45-1.6; p=0.59) were comparable. PFS was significantly longer in patients with a baseline natural killer (NK) cell count >100 cells/μl vs ≤100 cells/μl, (HR 0.16, 95% CI 0.06-0.42, p=0.0003). Infusion-related reactions (IRRs) were seen in 4/35 (11%) and 5/45 (11%) patients in the DLBCL and iNHL cohorts, mostly of grade 1-2 and duringthe first infusion of cycle 1. The incidence of grade ≥3 neutropenia, anemia and thrombocytopenia was 17%, 9% and 6% in DLBCL and 4%, 0% and 2% in iNHL patients, respectively. The incidence of MOR208 treatment-related serious adverse events was 6% in DLBCL and 4% in iNHL patients. No treatment-related deaths were reported.

Conclusions: MOR208 12 mg/kg showed encouraging preliminary single-agent activity in patients with R-R DLBCL or R-R iNHL, with long lasting responses, and was equally efficacious in NHL patients with rituximab refractory and non-refractory disease. Target lesion shrinkage was demonstrated in the majority of patients with SD. Patients with a high peripheral NK cell count at baseline benefited more from MOR208 treatment. MOR208 was generally well tolerated, with a favorable safety profile including patients on long-term treatment. The promising results of this trial further justify the development of MOR208 as part of a combination therapy in B-cell malignancies.