Two bispecific T-cell engagers have emerged as promising later-line treatment options for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), offering new hope for heavily pretreated patients who have exhausted conventional therapies. Epcoritamab-bysp (Epkinly) and glofitamab-gxbm (Columvi) both received FDA accelerated approval in 2023, marking a significant advancement in the treatment landscape for this aggressive lymphoma.
Mechanism and Clinical Implementation
Epcoritamab represents a novel CD20-binding bispecific agent that simultaneously targets CD20 on lymphoma cells and CD3 on T cells, bringing cytotoxic T cells into close proximity with cancer cells to exert cell-mediated cytotoxicity. Notably, epcoritamab binds to a distinct CD20 epitope different from rituximab or obinutuzumab, potentially offering activity in rituximab-refractory cases.
The drug's subcutaneous administration makes it particularly suitable for outpatient settings. "Epcoritamab is very feasible to give in the outpatient setting," explains Dr. Medhi H. Hamadani from Froedtert Hospital. The treatment protocol involves step-up dosing with the first two doses administered as outpatient procedures, while the third full dose is given in the hospital setting as a safety precaution.
Efficacy in Heavily Pretreated Populations
The EPCORE NHL-1 study (NCT03625037) provided the foundation for epcoritamab's accelerated approval, demonstrating impressive activity across multiple treatment lines. Whether administered in third, fourth, or fifth-line settings, overall response rates consistently exceeded 60%, with complete response rates around 40%.
Particularly noteworthy is the drug's performance in patients with CAR T-cell therapy failure. The study included 61 patients with prior CAR T-cell exposure, representing a substantially larger cohort than previous studies with loncastuximab tesirine (13 patients) or tafasitamab (20 patients). "There are almost 100 patients, including 61 with prior CAR, and the drug works in that setting," Hamadani noted.
Glofitamab: Fixed-Duration Alternative
Glofitamab offers a distinct approach with its intravenous administration and unique binding profile, targeting two CD20 molecules for every CD3 molecule. The NP30179 trial (NCT03075696) enrolled 150 patients with DLBCL and similar histologies, including 50 patients with prior CAR T-cell therapy.
The drug demonstrated overall response rates above 50% across all dose levels in this phase 1 dose escalation trial, with significantly better responses at approved phase 2 doses. A key advantage of glofitamab is its fixed-duration therapy approach, with treatment limited to one year before discontinuation.
Durability of Response
Recent landmark analyses have provided encouraging data regarding response durability. At the American Society of Hematology meeting, researchers presented data showing that among patients who completed one year of glofitamab therapy while in complete response, more than 70% remained in complete response one year after treatment discontinuation.
"Are these patients theoretically cured? No, but we are starting to ask this very provocative question: Is CAR T-cell therapy the only curative therapy for relapsed/refractory patients? Maybe not," Hamadani observed. "Bispecifics may become huge players in that setting."
Safety Profile and Management
Both agents demonstrate manageable safety profiles when appropriate protocols are implemented. Epcoritamab shows severe cytokine release syndrome (CRS) rates below 3%, though even grade 1 or 2 CRS requires careful management with established standard operating procedures and ready access to tocilizumab.
The dosing schedule for epcoritamab requires weekly administration for three months, followed by every-other-week dosing for six months, then monthly maintenance. While this schedule is cumbersome initially, it becomes more manageable over time and is feasible in community settings with proper protocols.
Clinical Implications
These bispecific T-cell engagers address a critical unmet need in DLBCL management, particularly for patients who have failed CAR T-cell therapy. Unlike CAR T-cell therapy, these agents offer off-the-shelf availability without the logistical complexities and manufacturing delays associated with personalized cellular therapies.
The emergence of these agents may reshape treatment sequencing decisions in relapsed/refractory DLBCL. For community oncologists managing CAR T-cell therapy failures, bispecific antibodies provide viable alternatives when traditional options like loncastuximab or tafasitamab prove ineffective.
Future Directions
The success of these bispecific T-cell engagers in later-line settings has prompted investigation of their potential in earlier treatment lines and combination strategies. Ongoing research focuses on optimizing dosing regimens, understanding resistance mechanisms, and exploring combinations with other immunotherapies.
As the field continues to evolve, these bispecific antibodies represent a paradigm shift in lymphoma treatment, offering the possibility of achieving durable responses and potentially curative outcomes in patients previously considered to have limited therapeutic options.
