SUMMARY: The FDA on May 19, 2023, granted accelerated approval to Epcoritamab-bysp (EPKINLY®) for relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, including DLBCL arising from indolent lymphoma, and High-Grade B-Cell Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.
DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.
Epcoritamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.
EPCORE NHL-1 is an ongoing, open-label, multi-cohort, multicenter, Phase 1/2b, single-arm trial in which the safety, tolerability, pharmacokinetics and preliminary efficacy of Epcoritamab in combination with standard-of-care (SOC) agents are being examined in patients with relapsed, progressive or refractory CD20+ mature B-cell Non-Hodgkin Lymphoma (NHL), including Diffuse Large B-Cell Lymphoma. Phase 1 of the trial consists of a first-in-human, dose-escalation portion, and Phase 2 is the expansion and optimization part.
The Phase 2 expansion cohort included 157 patients with relapsed/refractory Large B-Cell Lymphoma who were previously treated with a median of 3 lines of prior therapy. The median age was 64 years and median time from initial diagnosis was 1.6 yrs. Approximately 39% of patients had received prior CAR T-cell therapy, 20% had prior Autologous Stem Cell Transplantation, 61% had Primary refractory disease and 14% of patients with Diffuse Large B-Cell Lymphoma were confirmed Double Hit/Triple Hit by central FISH. Epcoritamab was administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity. Mitigation of Cytokine Release Syndrome included step-up dosing and corticosteroid prophylaxis in the first cycle alone. Step-up dosing was 0.16 mg on Day 1, 0.8 mg on Day 8, and 48 mg on Day 15 and Day 22 in Cycle 1, followed by fixed dosing of 48 mg weekly dosing during Cycles 2-3, every other week during Cycle 4-9, and then every four weeks on Day 1 of subsequent cycles. Per protocol, 24-hour hospitalization was required only for the first full dose (48 mg) to ensure close observation of patients. The Primary endpoint was Overall Response Rate (ORR) by Independent Review Committee. Key Secondary endpoints included the Duration of Response (DOR), time to response, Progression Free Survival (PFS), Overall Survival (OS), Complete Response (CR) rate, Safety, and tolerability.
At a median follow-up of 10.7 months, the Overall Response Rate for the total population was 63%, with a Complete Response Rate of 39%. The median Duration of Response was 12.0 months and was Not Reached among complete responders. Overall and Complete Response rates were similar across key prespecified subgroups. The median time to response was 1.4 months. MRD negativity was assessed by a ctDNA NGS assay and 46.4% were MRD negative at any time point on treatment. MRD negativity was reached at a median of 8 weeks for complete responders, and high MRD negativity rates were observed across all prespecified subgroups. MRD-negative responses were durable and correlated with PFS. The most common adverse events were Cytokine Release Syndrome (majority were Grade 1 or 2, with most events occurring after the first full dose), fever and fatigue. Immune effector Cell-Associated Neurotoxicity Syndrome occurred in 6.4% of patients.
It was concluded that subcutaneous single agent Epcoritamab is a convenient, off-the-shelf therapy that resulted in deep and durable responses, including high MRD negativity rates, with manageable safety, in highly refractory patients with Large B-cell lymphoma, including those with prior CAR T-cell exposure.
Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. Thieblemont C, Phillips T, Ghesquieres H, et al. J Clin Oncol. 2023;;41:2238-2247.
