Epcoritamab plus gemcitabine and oxaliplatin in transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma: how should this regimen be positioned in current treatment algorithms?

Transplant-ineligible Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL): an unresolved therapeutic challenge

R/R DLBCL remains a major therapeutic challenge, particularly for patients ineligible for autologous stem cell transplantation. Although recent advances, including chimeric antigen receptor T-cell (CAR-T) therapy and CD20 × CD3 bispecific antibodies, have markedly expanded the therapeutic armamentarium, a substantial proportion of patients are older, frail, or have comorbidities that preclude intensive cellular therapy. Moreover, even among technically eligible patients, the optimal sequencing of CAR-T therapy and bispecific antibodies remains uncertain. It is unclear which patients should preferentially receive CAR-T therapy, which may derive greater benefit from an off-the-shelf bispecific approach, and how these modalities should be positioned within a broader treatment trajectory. Paradoxically, the rapid development of effective immunotherapies has introduced new complexities, underscoring the need for additional data to more clearly define their optimal positioning strategies in transplant-ineligible R/R DLBCL.

Epcoritamab monotherapy: activity, durability, and remaining questions

CD20 × CD3 bispecific antibodies have demonstrated meaningful clinical activity in heavily pretreated patients with R/R DLBCL. Subcutaneous epcoritamab has emerged as a promising, off-the-shelf immunotherapeutic option. In the pivotal EPCORE NHL-1 trial, epcoritamab monotherapy achieved an overall response rate of approximately 63% and a complete response (CR) rate of 39% in patients with a median of three prior lines of therapy (1). At the 3-year follow-up, responses appeared durable; the median duration of response was 20.8 months, and the median duration of CR reached 36.1 months. Notably, among complete responders, the median progression-free survival (PFS) was 37.3 months, with approximately half of these patients remaining progression-free at 3 years (2). Furthermore, a clinical benefit was observed even in patients with high-risk features, including prior CAR-T cell exposure and primary refractory disease.

Cytokine release syndrome (CRS) was common but predominantly low-grade and typically occurred during early treatment cycles. Immune effector cell-associated neurotoxicity syndrome was infrequent, and immune effector cell-associated hematologic toxicity was generally reversible. Accordingly, these immune-mediated adverse events warrant careful consideration when this regimen is used in older or medically vulnerable populations.

Despite these findings, several questions remain unanswered. Although these response rates are notable, their durability appears heterogeneous, particularly in patients with high tumor burden or adverse biologic features. Moreover, continuous treatment until progression raises important considerations regarding cumulative toxicity, treatment burden, and cost. These observations provide a rationale for further exploration of combination strategies to deepen responses and potentially enhance long-term disease control.

EPCORE NHL-2: exploring a chemo-immunologic approach to possibly enhanced efficacy

Building upon the activity observed with epcoritamab monotherapy, the EPCORE NHL-2 trial evaluated its combination with gemcitabine and oxaliplatin (GemOx) in patients with transplant-ineligible R/R DLBCL (3). In this phase 1/2 study, the combination was associated with an overall response rate exceeding 80%, with CR reported in approximately 60% of treated patients. Notably, these outcomes were observed in a clinically challenging population that included individuals with primary refractory disease, prior CAR-T exposure, and double- or triple-hit lymphoma.

The activity observed with the EPCORE NHL-2 regimen supports the hypothesis that cytotoxic debulking may enhance the activity of bispecific therapy, although this remains speculative. While the regimen appeared clinically feasible, considerable hematologic and infectious toxicities were observed with the addition of epcoritamab to GemOx. Notably, more than 70% of patients experienced serious treatment-emergent adverse events (TEAEs), approximately 30% of patients discontinued treatment, and 13% experienced fatal TEAEs. With respect to specific adverse events associated with epcoritamab, CRS was frequent, although most events were low-grade, and severe neurotoxicity was uncommon; these findings appear broadly consistent with those reported with single-agent epcoritamab.

While cross-trial comparisons must be interpreted cautiously, the CR rate observed in EPCORE NHL-2 relative to monotherapy may suggest that a possible chemo-immunologic approach could offer complementary activity and warrants further study. These findings provide a rationale for continued investigation of combination strategies designed to enhance both the depth and durability of responses in transplant-ineligible R/R DLBCL.

Proposed mechanistic rationale for combining bispecific antibodies with chemotherapy

Several biologically plausible mechanisms have been proposed in preclinical and translational studies to support the combination of bispecific antibodies with chemotherapy. Cytotoxic chemotherapy may reduce tumor burden and antigen load, thereby alleviating T cell exhaustion and facilitating more effective immune synapse formation between T cells and malignant B cells (4). Furthermore, certain chemotherapeutic agents may transiently remodel the tumor microenvironment by depleting immunosuppressive myeloid populations, reducing regulatory T cell activity, and enhancing antigen presentation (5-8). Although these mechanisms remain incompletely understood in the context of R/R DLBCL, these findings may provide a preliminary rationale for further evaluation of this combination regimen.

Sequencing, duration, and cost: unanswered questions in the era of novel agents

Despite the potentially encouraging activity observed with epcoritamab-based combinations, several practical and strategic questions remain unresolved. The optimal sequencing of bispecific antibodies relative to CAR-T cell therapy, antibody-drug conjugates, and other emerging modalities has yet to be clearly defined. Although CAR-T therapy may offer the potential for durable, treatment-free remission in selected patients, its logistical complexity, manufacturing time, and toxicity profile may limit accessibility, particularly for many transplant-ineligible individuals. In contrast, bispecific antibodies provide an off-the-shelf option with broader applicability but typically require continued administration until disease progression.

Comparisons with other chemo-immunologic combinations further underscore the need for caution in cross-trial interpretations. For example, the STARGLO trial reported improved PFS with glofitamab plus GemOx compared with GemOx alone (9); however, important differences in patient populations complicate direct comparison with EPCORE NHL-2. The latter included a more heavily pretreated cohort, with a higher proportion of patients who had received ≥2 prior lines of therapy and prior CAR-T exposure. Therefore, definitive conclusions regarding relative efficacy will require mature data from well-designed phase III trials, interpreted within the context of differing patient populations and study designs.

The treatment duration and cost also merit further attention. Continuous therapy until progression, as employed in the EPCORE NHL-2 trial, may have implications for cumulative toxicity, financial burden, and patient preferences. Conversely, time-limited approaches may reduce long-term exposure but may also carry potential risks in terms of disease control. As the field continues to mature, balancing clinical efficacy with sustainability and healthcare resource utilization will become increasingly important.

Toward rational integration in the era of novel agents

In R/R DLBCL, the key challenge is the optimal positioning of bispecific antibodies within increasingly complex treatment algorithms. The EPCORE NHL-2 trial provides a preliminary clinical signal supporting the clinical feasibility of combining epcoritamab with GemOx in a transplant-ineligible population, although interpretation must remain cautious given the single-arm phase 1/2 design and the substantial treatment burden observed, particularly in this generally less-fit population.

Simultaneously, important questions remain regarding comparative value, optimal sequencing, treatment duration, patient selection, long-term feasibility, and cost-effectiveness. Identifying patients who may derive the greatest benefit from combination approaches versus bispecific monotherapy or cellular therapies will require continued prospective evaluation and real-world evidence. As the field evolves, individualized treatment strategies that integrate disease biology, patient fitness, and healthcare resources will be essential.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0457/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-0457/coif). The authors have no conflicts of interest to declare.

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