What Chemo-Free Immunotherapy Combos Have Potential in Indolent Lymphomas?

Lorenzo Falchi, MD, gave a presentation titled “Novel Immunotherapy Combinations in Indolent Lymphoma” at the Society of Hematological Oncology (SOHO) 2025 Annual Meeting. At the conference, he spoke with CancerNetwork® regarding the current landscape of combination therapies in indolent lymphomas.¹

When prompted about some of the most stand-out therapies, Falchi, an oncologist and hematologist specializing in lymphoma at the Memorial Sloan Kettering Cancer Center, highlighted several therapies. The first mentioned was the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), which evaluated epcoritamab (Epkinly) in combination with various other standard-of-care agents, including rituximab (Rituxan), lenalidomide, and bendamustine, in patients with B-cell non-Hodgkin lymphoma.²

In EPCORE NHL-2, he noted that high levels of complete responses (CRs) and progression-free survival were achieved.

Another mentioned trial was the phase 1 BP41072 trial (NCT04077723), which is evaluating the safety, tolerability, and efficacy of various regimens containing englumafusp alfa [CD19-4-1BBL] in patients with relapsed/refractory non-Hodgkin lymphoma.³ Notably, 79% of the patients with follicular lymphoma enrolled in the trial achieved a CR.

Transcript:

Lymphoma therapy, in general, is hardly ever a one-man show. It’s hardly ever a monotherapy, except for CAR T-cell therapy. Some of the more efficacious and powerful treatments for lymphoma in general, [and in] follicular lymphoma, are combinations of multiple anti-lymphoma drugs. This is also true for bispecific antibodies, and this is what I tried to outline in my presentation. For example, lenalidomide, which is an immunomodulating drug, has been a natural partner for bispecific antibodies alone or with rituximab, and the results with combined lenalidomide and bispecifics have been promising. Most patients achieve a CR.

In the study testing epcoritamab with rituximab and lenalidomide, we enrolled 111 patients. This is a large international…trial where we saw that 87% of the patients achieved a CR, and at 21 months of follow-up, 80% of the patients were progression-free. In addition to that, if one looks at the minimal residual disease [MRD]-negative response of patients who cleared their MRD, their chance of response and progression-free survival was even higher. This data suggested that the types of responses and the depth of responses with this combination were promising.

Other combinations have been tested. One that I am particularly excited about is with what’s called costimulatory bispecific antibodies—it’s a bispecific-bispecific duet. The first bispecific, the primary bispecific, was glofitamab [Columvi], and the second bispecific, the adjuvant or secondary bispecific, is the costimulatory…englumafusp alfa. It’s a promising drug because it attaches to the lymphoma cells, like the primary antibody, and to the T cell, delivering signal 2 to the T cell, and that boosts the T-cell activation and the ability to kill off the lymphoma cells.

That’s a beautiful theoretical concept, but the question was, “Is it going to work in clinical practice?” There has been a large first-in-human phase 1 trial internationally, demonstrating that 79% of the 24 enrolled patients with follicular lymphoma had a CR, and most of them held that response at a relatively long follow-up of almost 36 months. We have a sense that we can top the results of single-agent bispecific antibodies in multiple ways.

References

1. Falchi, L. Novel immunotherapy combinations in indolent lymphoma. Presented at the Society of Hematological Oncology 2025 Annual Meeting; September 2-6, 2025; Houston, TX.
2. Safety and efficacy trial of epcoritamab combinations in subjects with B-cell non-Hodgkin lymphoma (B-NHL) (EPCORE™ NHL-2). ClinicalTrials.gov. Updated September 3, 2025. Accessed September 22, 2025. https://tinyurl.com/24zaf59p
3. A study to evaluate the safety, pharmacokinetics and preliminary anti-tumor activity of englumafusp alfa in combination with obinutuzumab and in combination with glofitamab following a pre-treatment dose of obinutuzumab in participants with relapsed/​refractory B-cell non-Hodgkin’s lymphoma. ClinicalTrials.gov. Updated September 5, 2025. Accessed September 5, 2025. https://tinyurl.com/muedr6bt