How Bispecific Antibodies Are Transforming Frontline and Relapsed Lymphoma Treatment

The treatment landscape for B-cell lymphomas is transforming rapidly with bispecific antibodies (BsAbs) targeting CD20 and CD3, specifically in relapsed or refractory (R/R) patients for whom previously there had been limited options.

Agents such as epcoritamab (Epkinly; AbbVie and Genmab), mosunetuzumab (Lunsumio; Genentech, Inc), and glofitamab (Columvi; Genentech, Inc) have displayed high response rates and durable remissions in clinical trials. These therapies are being evaluated earlier in the treatment paradigm, signaling a potential shift toward frontline integration.¹^,²

Mechanism and Clinical Role of Bispecific Antibodies

The mechanism underlying BsAbs involves redirecting cytotoxic T-cell activity toward tumor cells, which simultaneously bind CD20 on malignant B cells and CD3 on T-cells. This mechanism stands apart from traditional monoclonal antibodies such as rituximab (Rituxan, Genentech, Inc.) as they enable immune-mediated tumor cell killing independent of major histocompatibility complex presentation.¹

These therapies have gained traction in patients with R/R diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) who are ineligible for or have progressed following CAR T-cell therapy. These patients commonly face poor outcomes with conventional salvage regimens, bringing attention to the clinical importance of bispecifics in these patients.²

Key Clinical Trial Findings in Relapsed/Refractory Disease

In clinical trials that evaluated the efficacy of bispecific antibodies, the data revealed promising results in heavily pretreated populations. In the EPCORE NHL-1 trial (NCT03625037) epcoritamab accomplished an overall response rate (ORR) of approximately 63% in patients with R/R DLBCL, with a complete response (CR) rate surpassing 35%.³ Likewise, in the NP30179 phase 1/2 study of Glofitamab in R/R DLBCL (NCT06552572), the result was an ORR of 52% and CR rates near 39% in a comparable patient population.⁴

In the GO29781 phase 1/2 trial (NCT02500407), Mosunetuzumab demonstrated strong activity, particularly in follicular lymphoma, with durable responses and a favorable safety profile that supports outpatient administration.⁵ The data gathered found that cytokine release syndrome (CRS), a common toxicity associated with T-cell–engaging therapies, was generally low grade and manageable with step-up dosing strategies across studies.³–⁵

Emerging Role in Earlier Lines of Therapy

While bispecific antibodies are currently approved primarily for R/R disease, there is ongoing research being evaluated in order to see efficiency in earlier lines of therapy. Several trials such as EPCORE NHL-2 (NCT04663347) and NP40126 (NCT03467373) are evaluating these agents in combination with standard chemoimmunotherapy regimens, such as R-CHOP, in newly diagnosed DLBCL.¹

This collection of early phase data implies the incorporation of bispecifics into frontline therapy may enhance response depth and durability while potentially reducing reliance on cytotoxic chemotherapy. If ever validated through larger studies, this approach has the potential to redefine the standard of care and expand access to highly active immunotherapies earlier in the disease course.²

Pharmacist Implications

With the expansion of bispecific antibodies comes several important considerations for practitioners. It is critical to have familiarity with step-up dosing protocols and CRS mitigation strategies as early identification and management of immune-related toxicities can significantly impact patient outcomes.³

The outpatient administration of agents such as mosunetuzumab comes with a shift that introduces new workflow considerations, which can include patient monitoring, coordination of care, and education on symptom recognition.⁵ Pharmacists are well positioned to ensure that patients are utilizing the appropriate premedication, adhering to required dosing schedules, and managing adverse effects.

With more research analyzing bispecific antibodies moving into earlier lines of therapy, it is essential for pharmacists and healthcare practitioners to remain informed about evolving clinical data, combination strategies, and payer considerations that may influence access and utilization. The integration of these therapies represents not only a clinical advancement but also an operational shift in lymphoma care delivery.

References

1.Hutchings M, Morschhauser F, Iacoboni G, et al. Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial. J Clin Oncol. 2021;39(18):1959-1970. doi:10.1200/JCO.20.03175

2.Budde LE, Assouline S, Sehn LH, et al. Durable Responses With Mosunetuzumab in Relapsed/Refractory Indolent and Aggressive B-Cell Non-Hodgkin Lymphomas: Extended Follow-Up of a Phase I/II Study. J Clin Oncol. 2024;42(19):2250-2256. doi:10.1200/JCO.23.02329

3.Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653-2662. doi:10.1038/s41375-024-02410-8

4.Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;387(24):2220-2231. doi:10.1056/NEJMoa2206913

5.Sehn LH, Bartlett NL, Matasar M, et al. P1078: MOSUNETUZUMAB DEMONSTRATES DURABLE RESPONSES IN PATIENTS WITH RELAPSED AND/OR REFRACTORY FOLLICULAR LYMPHOMA WHO HAVE RECEIVED ≥2 PRIOR THERAPIES: UPDATED ANALYSIS OF A PIVOTAL PHASE II STUDY. Hemasphere. 2023;7(Suppl ):e36694eb. Published 2023 Aug 8. doi:10.1097/01.HS9.0000971208.36694.eb