CD3×CD20 bispecifics + chemotherapy: good news for R/R DLBCL

In this issue of Blood, Brody et al¹ present the initial analysis from arm 5 of the EPCORE NHL-2 trial, using the CD3×CD20 bispecific antibody epcoritamab plus GemOx in transplant-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).

The treatment for R/R DLBCL has markedly improved over the past decade with the advent of novel immunotherapies.^2,3 However, patients who are ineligible for transplantation due to age, comorbidities, or performance status still have an unmet medical need. Although chimeric antigen receptor T-cell (CAR-T) therapies have significantly improved long-term survival and cure rates for R/R DLBCL, their impact remains limited in the transplant-ineligible population.^4,5 

This phase 1b/2 study enrolled 103 patients with a median age of 72 years, who had received a median of 2 previous lines of therapy. Most patients exhibited high-risk features: 52% were primary refractory, 70% were refractory to their last treatment, 61% had stage IV disease, and 28% had previous CAR-T therapy. The study therapy included epcoritamab, administered until disease progression, and the 4 cycles of the gemcitabine-oxaliplatin (GemOx) regimen. The complete remission rate was an impressive 61%. With a median follow-up of 13.2 months, the epcoritamab/GemOx therapy demonstrated in the combined population a median duration of complete remission, progression-free survival, and overall survival of 23.6 months, 11.2 months, and 21.6 months, respectively. Although these figures appear superior to those achieved with either epcoritamab alone or GemOx alone, the short follow-up duration requires that the results be interpreted with caution. The combination therapy's safety profile showed no unexpected toxicities. The most common grade ≥3 treatment-emergent adverse events included cytopenias: thrombocytopenia (59%), neutropenia (57%), anemia (43%), and infections (29%).

Bispecific antibodies in cancer immunotherapy are engineered to target 2 distinct antigens: 1 binding site engages a tumor antigen and the other engages the CD3 portion of the T-cell receptor complex.⁶ By simultaneously binding CD3 and a tumor antigen, bispecifics establish a stable immunological synapse that activates T-cells, leading to tumor cell lysis through cytotoxic granule release and cytokine and chemokine secretion, enhancing T-cell recruitment. Bispecific antibodies are “off-the-shelf” therapies that address challenges associated with CAR-T therapy, such as the need for bridging therapy and lymphodepletion before CAR-T infusion, complex manufacturing, and patient selection limited to those with slowly progressing disease or whose disease is responsive to bridging therapy.

Several CD3×CD20 bispecific antibodies are currently being used for treatment of lymphoma. Glofitamab,⁷ epcoritamab,⁸ odronextamab,⁹ and mosunetuzumab¹⁰ have been approved for treating adults with R/R DLBCL or follicular lymphoma after at least 2 lines of systemic therapy.

Epcoritamab is notable for its administration until disease progression, which is expected to enhance long-term disease control and convert initial stable disease into partial or complete remission. In arm 5 (patients with R/R DLBCL who were ineligible for or had failed autologous stem cell transplant) of the EPCORE NHL-2 trial, the median duration of epcoritamab treatment was 8.3 (range, 0.3 to 33.2) months. Response conversion occurred in 3 patients with stable disease who achieved partial or complete remission after week 12, suggesting a potential for late responses, although only in a few patients. Notably, among the 59 patients who stopped therapy, 32 did so due to disease progression, with all but 2 receiving epcoritamab at the time of progression. This observation raises critical questions regarding the benefit of continuing epcoritamab treatment until progression. Complete data on the disease status (complete remission, partial remission, stable disease) before progression will be crucial to evaluate this issue.

The nonrandomized design and short follow-up are key limitations to the study. Although the high complete remission rate is a robust finding, the median duration of complete remission, progression-free survival, and overall survival require more mature data and a more extensive minimal residual disease assessment. Extended follow-up will also provide a more complete evaluation of the safety profile of epcoritamab when combined with chemotherapy.

Despite these limitations, the efficacy and safety seen in arm 5 of the EPCORE NHL-2 trial highlight the potential of epcoritamab combined with chemotherapy as a clinically meaningful option for R/R DLBCL patients. Beyond their combination with chemotherapy regimens, bispecific antibodies are also explored in novel non-chemotherapy combinations to reduce toxicity while increasing efficacy. These combinations leverage the unique ability of bispecifics to harness T-cell activation and tumor targeting in synergy with other agents, such as checkpoint inhibitors, novel agents triggering costimulatory signals, or targeted therapies. The versatility of bispecifics as an “off-the-shelf” treatment, coupled with their ability to integrate into diverse therapeutic strategies, positions them as a cornerstone in the evolving landscape of R/R DLBCL management, offering hope for durable remissions with less reliance on traditional cytotoxic agents.

Conflict-of-interest disclosure: C.C.-S. has had an advisory role and has received honoraria from AbbVie and Genmab.