Early Data Support Off-the-Shelf Englumafusp Alfa/Glofitamab in B-NHL

Adding the CD19–4-1BB costimulatory fusion protein englumafusp alfa to the bispecific antibody glofitamab (Columvi) demonstrated encouraging response rates and a manageable safety profile in patients with relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL), according to results from part 2 of the phase 1 BP41072 trial (NCT04077723) published in Nature Medicine.¹

In the cohort of patients with aggressive B-NHL who began englumafusp alfa on cycle 2, day 8 (C2D8; n = 83), the overall response rate (ORR) was 68.7% (95% CI, 57.6%-78.4%) and the complete metabolic response (CMR) rate was 56.6% (95% CI, 45.4%-67.9%). Among patients without prior exposure to chimeric antigen receptor (CAR) T-cell therapy (n = 41), the ORR and CMR rates rose to 73.2% (95% CI, 57.1%-85.8%) and 65.9% (95% CI, 50.1%-81.6%), respectively.

The safety profile of the regimen was determined consistent with glofitamab monotherapy. Adverse events (AEs) of any grade occurred in 98.5% of all safety-evaluable patients (n = 134), with grade 3/4 AEs in 59.0% and serious AEs in 62.7%. The maximum tolerated dose of englumafusp alfa was not reached, and 1 dose-limiting toxicity—grade 5 Pneumocystis jirovecii pneumonia—was reported. Grade 5 AEs occurred in 10 patients (7.5%) overall.

Cytokine release syndrome (CRS) was the most common AE (55.2%) and was predominantly low grade, occurring mainly during glofitamab step-up dosing before englumafusp alfa was introduced. Other frequent AEs included anemia (33.6%) and COVID-19 (32.8%). Neutropenia was the most common grade 3/4 event (24.6%). A single, nonserious, grade 1 immune effector cell-associated neurotoxicity syndrome event was reported.

“Our findings support the principle of T cell co-stimulation to elicit increased T cell persistence, analogous to the mode of action of second-generation CAR T cell therapies,” lead author Martin Hutchings, MD, PhD, and colleagues wrote in the publication.

The updated results reported in Nature Medicine largely reinforce the activity signal first reported during the 2024 European Hematology Association (EHA) Congress. Here, the safety profile was similarly consistent with glofitamab monotherapy. Dose-escalation results as of October 25, 2023, showed a best overall response (BOR) of 67.0% and a complete response (CR) rate of 57.0% among 83 patients with relapsed/refractory aggressive B-NHL in the second-line and beyond setting; in the third-line and beyond setting, the BOR was 65.7% and the CR rate was 52.8%.

Phase 1 Study Design and Patient Characteristics

The BP41072 study is a phase 1/2, open-label, nonrandomized study evaluating the safety, tolerability, and preliminary efficacy of englumafusp alfa.² The study enrolled 134 patients with R/R B-NHL across 15 sites in Australia, Belgium, Denmark, France, Italy, Spain, the United Kingdom, and the United States between September 2020 and July 2023.

Of the total study population, 109 patients had aggressive B-NHL—including diffuse large B-cell lymphoma (DLBCL; n = 78), transformed follicular lymphoma (n = 23), and other subtypes—and 25 had indolent B-NHL. The median number of prior therapies was 3 (range, 1-8), and 58 patients (43.3%) had received prior CAR T-cell therapy.

All patients received obinutuzumab pretreatment 7 days before the first glofitamab dose to mitigate CRS risk. Glofitamab was given over 12 cycles with step-up dosing in cycle 1, reaching a 30-mg target dose from cycle 2 onward. Englumafusp alfa was administered at escalating doses starting either on cycle 2, day 8 or, in later cohorts, during glofitamab step-up dosing on cycle 1, day 10. The former schedule was ultimately selected for further development based on a more favorable benefit-risk profile.

An Off-the-Shelf Alternative to Cellular Therapy

As described by the authors, the “pure immunotherapy” approach of the regimen avoids chemotherapy-related toxicities, which may make it particularly attractive for elderly patients or those unfit for intensive chemotherapy due to comorbidities.

Furthermore, unlike autologous CAR T-cell products, which require individualized cell manufacturing, both englumafusp alfa and glofitamab are administered as ready-to-use infusions. This feature avoids the logistical steps associated with cellular therapy and positions the regimen as a potential off-the-shelf alternative to CAR T.

Larger, controlled studies will be needed to define this combination's role relative to existing treatment options for patients with R/R B-NHL. A dose-expansion phase of the trial is ongoing.

REFERENCES

1. Hutchings M, Dickinson M, Gritti G, et al. Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial. Nature Medicine. Published online July 16, 2026. doi:10.1038/s41591-026-04533-0

2. 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 May 29, 2026. Accessed July 16, 2026. https://clinicaltrials.gov/study/NCT04077723