Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma with the Bispecific T-Cell Engager (BiTE®) Antibody Construct Blinatumomab: Primary Analysis Results from an Open-Label, Phase 2 Study
Authors: Viardot Andreas , Goebeler Mariele , Hess Georg , Neumann Svenja , Pfreundschuh Michael , Adrian Nicole , Zettl Florian , Libicher Martin , Degenhard Evelyn , Stieglmaier Julia , Zhang Alicia , Nagorsen Dirk , Bargou Ralf C. 
Published: October 2019

Abstract
Introduction: Treatment of relapsed or refractory DLBCL can be challenging and little progress has been made in recent years. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct, engages CD3+ cytotoxic T cells, resulting in T-cell expansion and lysis of CD19+ B cells. In a prior phase 1 study, blinatumomab treatment resulted in an overall response rate (ORR) of 55% in a subset of patients with diffuse large B-cell lymphoma (DLBCL). In the present phase 2 study, we compared stepwise versus flat dosing of blinatumomab, and evaluated its efficacy in patients with relapsed/refractory (r/r) DLBCL.
Methods: Eligible patients were ≥18 years of age, had an Eastern Cooperative Oncology Group performance status ≤2 and had DLBCL; patients were refractory to treatment, had relapsed following autologous HSCT, or had relapsed and were ineligible for autologous hematopoietic stem cell transplantation (HSCT). Blinatumomab was administered over 8 weeks by continuous intravenous infusion. In stage 1, stepwise dosing (cohort I: 9, 28, and 112 μg/day after weeks 1, 2, respectively) was compared to constant dosing of 112 μg/day (cohort II). Based on the benefit/risk assessment from stage 1, stepwise dosing (9, 28, and 112 μg/day) was chosen for cohort III in stage 2. Patients achieving response after 8 weeks of treatment could receive a 4-week consolidation cycle after a 4-week treatment-free period. All patients received prophylactic dexamethasone (2 × 20 mg before infusion start and at infusion start; 3 × 8 mg/day for the first 2 days after infusion start and at dose step). The primary endpoint was ORR by Cheson revised response criteria for malignant lymphomas. Response was evaluated by independent radiologic assessment.
Results: As of the primary analysis, 25 patients have been enrolled and treated: 9, 2, and 14 in cohorts I, II, and III, respectively. Fifty-six percent of patients were men, and the median age was 66 years (range, 34–85). Seven (28%) patients had received prior autologous HSCT. Blinatumomab was received as a fourth-line systemic therapy following a median (range) of 3 (1-7) prior treatments. Median (interquartile range) duration of exposure for stepwise dosing (cohorts I and III) was 46.8 (22.1−76.9) days. Twenty-one patients were evaluable for response (cohort I, n=7; cohort II, n=1; cohort III, n=13). Four patients were not evaluable for ORR per protocol definition due to early treatment discontinuation (<1 week on target dose in absence of disease progression): 1 discontinued due to investigator’s decision and 3 discontinued due to AEs. Fourteen patients have died (cohort I, n=5; cohort II, n= 1; cohort II, n=8). Eleven deaths were due to disease progression, one patient died of cardiogenic shock and one from organ failure following transplantation; no cause of death was reported for one patient. Among the evaluable 21 patients, 9 patients responded (4 CRs, 5 PRs) resulting in an ORR of 43%. All patients who responded did so within the first 8-week cycle. Among responders (n=9), median duration of response was 11.6 months. All patients experienced ≥1 adverse event (AE). Regardless of causality and grade, the most common AEs were tremor (52%), pyrexia (44%), diarrhea (24%), fatigue (24%), edema (24%), and pneumonia (24%). Twenty-four (96%) and 5 (20%) patients had grade 3 and 4 AEs, respectively. Serious AEs occurred in 23 (92%) patients, regardless of causality; the most common were pneumonia (24%), device-related infection (16%), and pyrexia (16%). Two patients had fatal on-study AEs (pneumonia and disease progression), assessed as unrelated to blinatumomab. Seven patients (cohort I, n=3; cohort II, n=2; cohort III, n=2) had grade 3 neurologic AEs (grade 3 AEs occurring in >1 patient were disorientation, encephalopathy, aphasia, and epilepsy [n=2 each]). There were no grade 4 or 5 neurologic events.
Conclusions: In this phase 2 study, a stepwise dosing regimen (9, 28, and 112 μg/day) was established as the preferred dosing for blinatumomab in DLBCL. Treatment with blinatumomab showed an acceptable safety profile and resulted in objective and durable responses in heavily pretreated patients with r/r DLBCL.

Disclosures
Viardot: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Travel support Other; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel support, Travel support Other; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Travel support Other. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Libicher:Amgen Inc.: Consultancy. Degenhard:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Stieglmaier:Amgen Inc.: Equity Ownership; Amgen Research (Munich) GmbH: Employment. Zhang:Amgen Inc.: Employment. Nagorsen:Amgen Inc.: Blinatumomab-related Patents & Royalties, Employment, Equity Ownership. Bargou:Amgen Inc.: Consultancy, Honoraria.