The FDA has approved two groundbreaking bispecific T-cell engaging antibodies for patients with relapsed or refractory B-cell lymphomas, marking a significant advancement in treatment options for this aggressive cancer type. These approvals represent new mechanisms of action for patients who have exhausted multiple prior treatment lines.
Epcoritamab Becomes First T-Cell Engaging Bispecific Antibody
The FDA granted accelerated approval to epcoritamab-bysp (Epkinly) for adult patients with relapsed/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 therapies. This marks the first T-cell engaging bispecific antibody approved for this indication.
The approval is supported by findings from the phase 1/2 EPCORE NHL-1 trial, which enrolled 148 patients with CD20-positive DLBCL in the expansion cohort. The study demonstrated an overall response rate of 61% (95% CI, 53%-69%), including a complete response rate of 38%. At a median follow-up of 9.8 months in responders, the median duration of response was estimated to be 15.6 months (95% CI, 9.7-not reached).
"Patients with DLBCL who relapse or are refractory to currently available therapies have limited options. Generally, the prognosis for these patients is poor and management of this aggressive disease can be challenging," said Tycel Philips, MD, associate professor in the Division of Lymphoma at City of Hope. "Epcoritamab is a subcutaneous bispecific antibody that offers an additional treatment option for this patient population."
Treatment Protocol and Patient Population
Epcoritamab is administered using a step-up dosing regimen in cycle 1, comprising 0.16 mg on day 1, 0.8 mg on day 8, and 48 mg on days 15 and 22. This is followed by a fixed weekly dose of 48 mg during cycles 2 to 3, an every-other-week dose for cycles 4 to 9, and then every four weeks thereafter.
The trial enrolled patients with heavily pretreated disease, with a median of 3 prior lines of treatment (range 2-11). Notably, 39% of patients had prior exposure to CAR T-cell therapy, and 29% were refractory to this modality. The majority of patients (82%) were refractory to their last treatment.
Glofitamab Adds to Treatment Arsenal
The FDA also granted accelerated approval to glofitamab-gxbm (Columvi) for select patients with B-cell lymphoma whose disease did not respond to or relapsed following two or more lines of systemic therapy. The indication covers DLBCL not otherwise specified and large B-cell lymphoma arising from follicular lymphoma.
The approval was based on results from the open-label, multicenter, single-arm NP30179 trial involving 132 patients. The study showed an overall response rate of 56%, with 43% of patients experiencing complete responses. The estimated median duration of response was 18.4 months.
Safety Profile and Warnings
Both therapies carry boxed warnings for serious or life-threatening immune-related adverse reactions. In the epcoritamab trial, 51% of patients experienced cytokine release syndrome (CRS) and 6% had immune effector cell-associated neurotoxicity syndrome (ICANS). Among those with CRS, the condition was grade 1, 2, and 3 in 37%, 17%, and 2.5% of patients, respectively.
The most common toxicities with epcoritamab included CRS, fatigue, musculoskeletal pain, injection site reactions, pyrexia, abdominal pain, nausea, and diarrhea. Laboratory abnormalities of grade 3-4 severity included decreased lymphocyte, neutrophil, and white blood cell counts, as well as reduced hemoglobin and platelet counts.
Clinical Impact and Future Directions
These bispecific T-cell engagers join a growing list of BiTE therapies for hematologic malignancies, including blinatumomab (Blincyto), teclistamab (Tecvayli), and mosunetuzumab (Lunsumio). Both work by binding the CD3 receptor on T cells and the CD20 antigen highly expressed on B-cell lymphoma cells.
"The FDA approval of epcoritamab represents a new treatment mechanism of action for third line patients with DLBCL. As a non-chemotherapy, single-agent treatment for this population, we hope that epcoritamab can effectively treat this aggressive cancer type and can be used for patient care quickly and in an off the shelf form for physicians," said Thomas Hudson, MD, senior vice president of research and development at AbbVie.
DLBCL accounts for 30-40% of all non-Hodgkin lymphoma cases, with approximately 80,550 individuals expected to be diagnosed with non-Hodgkin lymphoma in the U.S. in 2023. Both accelerated approvals may be contingent upon confirmatory trials demonstrating continued clinical benefit.
