Novel Bispecific Antibody Combinations Show Promise in Indolent Lymphoma Treatment
Key Insights
Bispecific antibodies demonstrate comparable efficacy to standard-of-care therapies in indolent lymphoma (search), with 87% complete response rates observed in a large international phase 2 trial combining epcoritamab with rituximab and lenalidomide.
Five randomized controlled trials are currently evaluating chemotherapy-free bispecific antibody combinations against standard chemoimmunotherapy, potentially eliminating the need for cytotoxic conventional chemotherapy.
Novel combination approaches, including costimulatory bispecific antibodies, show enhanced T-cell activation with 79% complete response rates in follicular lymphoma (search) patients.
Lorenzo Falchi, MD, an oncologist and hematologist specializing in lymphoma at Memorial Sloan Kettering Cancer Center, presented compelling evidence at the Society of Hematological Oncology (SOHO) 2025 Annual Meeting demonstrating that novel immunotherapy combinations in indolent lymphoma (search) are achieving efficacy rates that rival current standard-of-care treatments.
Bispecific Antibodies Demonstrate Strong Clinical Performance
The most significant finding presented was that bispecific antibodies, while novel, are well-understood from a pharmacokinetic perspective due to their immunoglobulin-like molecular structure. "They are adaptable, versatile, and easy to combine with a variety of partner chemotherapy or immunotherapy agents," Falchi explained. Their distinct modes of action and largely non-overlapping toxicity profiles make them particularly suitable for combination therapies.
Clinical data supports this promise. In a large international phase 2 trial testing epcoritamab with rituximab and lenalidomide, 111 patients were enrolled with remarkable results: 87% achieved complete response (CR), and at 21 months of follow-up, 80% of patients remained progression-free. Patients who achieved minimal residual disease (MRD)-negative responses showed even higher rates of response and progression-free survival.
Paradigm Shift in Treatment Approach
The traditional medical school teaching that patients with indolent lymphoma (search) and follicular lymphoma (search) have diminishing response rates and shorter durations of benefit with each subsequent therapy line appears to be changing. "In the novel era of T-cell-based immunotherapies, we are witnessing a paradigm shift where patients now experience much longer durations of benefit, with much higher complete response rates and much deeper responses," Falchi noted.
MRD testing reveals that most patients achieving radiographic CR also demonstrate clearance of their MRD, indicating the power of chemotherapy-free approaches for treating this prevalent lymphoma.
Innovative Combination Strategies
Beyond traditional combinations, researchers are exploring costimulatory bispecific antibodies—what Falchi describes as a "bispecific-bispecific duet." This approach combines glofitamab as the primary bispecific with englumafusp alpha (search) (CD19 (search)-4-1BBL (search)) as the costimulatory component. The secondary bispecific attaches to both lymphoma cells and T cells, delivering signal 2 to boost T-cell activation and enhance lymphoma cell killing capability.
Clinical results from a first-in-human phase 1 trial demonstrated that 79% of 24 enrolled follicular lymphoma (search) patients achieved CR, with the majority maintaining response at nearly 36 months of follow-up.
Expanding Clinical Trial Landscape
Currently, five separate randomized controlled trials internationally are testing chemotherapy-free bispecific combinations against standard-of-care chemoimmunotherapy, both in relapsed and frontline settings. "I am hopeful that we can not only challenge, but beat, the current standard of care, and, once and for all, get rid of cytotoxic conventional chemotherapy for these patients," Falchi stated.
Managing Emerging Toxicities
While bispecific antibodies share some toxicity profiles with CAR T-cell therapy, including cytokine release syndrome (CRS) and potential neurotoxicity, these complications are generally less frequent and less severe. However, infectious disease complications have emerged as a significant concern, with most infections being respiratory, viral, or bacterial in nature.
Falchi's center has developed proactive management strategies, including Varicella-Zoster Virus prophylaxis with acyclovir or valacyclovir, pneumocystis jirovecii pneumonia prophylaxis, and low-threshold use of intravenous immunoglobulin replacement due to commonly observed low IgG levels. "There's emerging data that suggests that there is a non-relapse mortality risk associated with bispecific antibodies, and that's primarily driven by infections," he emphasized.
Future Optimization Challenges
Despite the promising efficacy data, several areas require improvement. One significant challenge is the phenomenon of pseudo-progression, where PET scans may show inflammation induced by immune system activation as disease progression. This can lead to misinterpretation of treatment response, highlighting the need for better biomarkers such as MRD assessment in conjunction with radiographic imaging.
Treatment duration optimization also presents an opportunity. Current randomized trials design treatment courses lasting over two years, including 4-6 months of induction followed by 18 months to 2 years of maintenance. Given the deep responses observed, researchers question whether all patients require such extended therapy with its associated immunosuppression and infection risks.
The field stands at a critical juncture where the success of these novel combinations may fundamentally change the treatment paradigm for indolent lymphoma (search), potentially eliminating the need for conventional cytotoxic chemotherapy while addressing the emerging challenges of infection management and treatment optimization.