Single-Arm Phase II Study of MOR208 Combined with Lenalidomide in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: L-Mind

Introduction: The B-lymphocyte antigen CD19 is broadly and homogeneously expressed across different B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), and enhances B-cell receptor signaling and tumor cell proliferation. MOR208 is an Fc-enhanced, humanized, monoclonal antibody that targets CD19 on tumor cells leading to natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity, macrophage-mediated antibody-dependent cell-mediated phagocytosis and direct cytotoxicity. The immunomodulatory drug, lenalidomide (LEN), has both antiproliferative and antiangiogenic effects, and can stimulate the activity of immune effectors, such as NK cells. In clinical studies, both MOR208 and LEN have demonstrated single agent activity in patients with relapsed or refractory (R-R) DLBCL. In addition, MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing, multicenter phase II study was designed to assess the safety and efficacy of MOR208 combined with LEN in patients with R-R DLBCL (NCT02399085).

Methods:Patients >18 years of age with R-R DLBCL, an Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function, who have relapsed after or are refractory to at least one but not more than three prior systemic therapies, including at least one CD20-targeting regimen, and who are not candidates for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), are eligible. Patients with primary refractory disease are excluded. Treatment comprises up to 12, 28-day cycles of MOR208 12 mg/kg, administered by intravenous (IV) infusion, weekly during cycles 1-3 (loading dose day 4 of cycle 1) and every second week during cycles 4-12 plus LEN 25 mg administered orally, days 1-21 of each cycle. Patients progression-free after 12 cycles may receive up to 12 additional cycles of MOR208 12 mg/kg IV, administered every second week. The primary endpoint is objective response rate (ORR), centrally assessed, as per the International Working Group criteria, 2007. Secondary endpoints include duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers.

Results: As of June 13, 2017, 51 patients had been enrolled. 44 patients qualified for the assessment of response (median follow-up 5.5 months), with the 7 remaining patients under treatment prior to their initial post-baseline response assessment. Median age was 73.5 years (range 47-82); 24 (47%) had received ≥2 prior lines of therapy; 18 (35%) had rituximab refractory disease; 30 (59%) had Ann Arbor stage ≥III disease; 28 (55%) had an elevated lactate dehydrogenase level, and 24 (47%) had an International Prognostic Index of 3 to 5 indicating poor prognosis. The most common treatment-emergent adverse events (any grade/grade ≥3) were neutropenia, 19/18 (37%/35%) of 51 patients, anemia, 12/2 (24%/4%), thrombocytopenia, 11/5 (22%/10%), diarrhea 11/0 (22%/0%), rashes, 10/3 (20%/6%) and pyrexia 9/1 (18%/2%). Treatment-related serious adverse events occurred in 8 (16%) patients (pneumonia, febrile neutropenia, agranulocytosis, bronchitis, tumor flare, pyrexia, asthenia, pulmonary embolism, arthritis). No infusion-related reactions were reported for MOR208; 23 (45%) patients required a LEN dose reduction. Based on investigator assessments, complete and partial responses were seen in 14 (32%) and 9 (20%) of 44 patients, respectively, summing to an ORR of 52%. 19 (83%) of 23 responders are still in remission. A further 6 (14%) of 44 patients had stable disease. The median time to response was 1.8 months; the median time to complete response was 2.3 months and the preliminary median progression-free survival (PFS) is 11.3 months (95% confidence interval: 5.4 months - not reached).

Conclusions: In this preliminary analysis of an ongoing study, MOR208 in combination with LEN has shown encouraging activity in patients with R-R DLBCL who were ineligible for HDC and ASCT and who therefore had a poor prognosis. The combination resulted in a notable prolongation of PFS, when compared with historical data for other regimens. MOR208 plus LEN was generally well tolerated, with only 45% of patients requiring a reduction in the LEN dose due to toxicity. Accrual, treatment and follow-up of patients are currently ongoing, as are cell of origin and other biomarker analyses.