Englumafusp Alfa Combo Shows Encouraging Activity in B-Cell Lymphoma

The addition of englumafusp alfa to glofitamab (Columvi) displayed encouraging efficacy and a safety profile consistent with glofitamab monotherapy in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to results from part 2 of the phase 1 BP41072 trial (NCT04077723) published in Nature Medicine.

The maximum tolerated dose (MTD) of englumafusp alfa was not reached, and 1 dose-limiting toxicity occurred: a grade 5 Pneumocystis jirovecii pneumonia event. Any-grade adverse events (AEs) were reported in 98.5% of patients, with grade 3/4 AEs in 59.0% and grade 5 AEs in 10 patients (7.5%). The most common AEs were cytokine release syndrome (CRS; 55.2%), anemia (33.6%), and COVID-19 (32.8%). CRS was predominantly low grade, with grade 1 events occurring in 48.5% of patients, which occurred mainly during glofitamab step-up dosing before englumafusp alfa administration.

In the cycle 2, day 8 (C2D8) cohort of patients with aggressive B-NHL (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 CAR T-cell therapy exposure (n = 41), 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 median progression-free survival (PFS) in the C2D8 cohort was 9.7 months (95% CI, 4.9-25.1), with a 12-month PFS rate of 45.8% (95% CI, 34.7%-56.8%); median overall survival (OS) was 24.1 months (95% CI, 12.6-not estimable), with a 12-month OS rate of 63.0% (95% CI, 52.5%-73.5%). In patients with indolent B-NHL in the C2D8 cohort (n = 24), the ORR was 91.7% (95% CI, 73.0%-99.0%), and the CMR rate was 79.2% (95% CI, 60.8%-97.5%).

“The combination of englumafusp alfa plus glofitamab was well-tolerated at all dose levels explored, and was consistent with the known safety profile of glofitamab monotherapy, with no new or synergistic safety signals,” lead author Martin Hutchings, MD, PhD, clinical professor in the Department of Clinical Medicine at the Copenhagen University of Hospital, wrote in the publication with study coinvestigators. “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. Leveraging this principle, the combination of englumafusp alfa and glofitamab offers a potential off-the-shelf alternative to CAR T-cell therapies.”

BP41072 is an ongoing, open-label, multicenter, phase 1/2 dose-escalation and dose-expansion study. Part 2, reported here, was a nonrandomized, phase 1 dose-escalation study of englumafusp alfa—a CD19–4-1BBL co-stimulatory antibody-like fusion protein designed to augment T-cell activation and limit T-cell exhaustion—in combination with glofitamab, a CD20×CD3 bispecific antibody. Investigators enrolled 134 patients, including 109 with aggressive B-NHL and 25 with indolent B-NHL, across 15 sites in Australia, Belgium, Denmark, France, Italy, Spain, the UK, and the US. Patients had relapsed after or were nonresponders to at least 1 prior line of therapy; 58 patients (43.3%) had received prior CAR T-cell therapy.

Patients received obinutuzumab (Gazyva) pretreatment 7 days before the first glofitamab dose to mitigate CRS risk, followed by glofitamab step-up dosing in cycle 1 and 11 subsequent cycles of glofitamab plus englumafusp alfa. In dose-escalation cohorts, englumafusp alfa was started on C2D8; in later cohorts, it was started earlier, during glofitamab step-up dosing on cycle 1 day 10 (C1D10), to explore an earlier co-stimulatory signal. The C2D8 schedule was ultimately selected for further development.

The coprimary end point of the study were the MTD as well as the safety and tolerability of englumafusp alfa plus glofitamab. Secondary end points included antitumor activity, pharmacokinetics, pharmacodynamics, and the mechanism of action.

Pharmacodynamic analyses showed that englumafusp alfa induced a dose-dependent expansion of peripheral CD8-positive effector memory T cells while reducing expansion of exhaustion-associated T-cell phenotypes. Lower composite pharmacodynamic scores, reflecting greater on-target effect, were significantly associated with CMR, deeper circulating tumor DNA responses, and improved PFS, supporting the drug's intended co-stimulatory mechanism.

The authors noted that outcomes in patients with 2 or more prior lines of therapy were generally comparable with those reported for the CAR T-cell therapy lisocabtagene maraleucel (Breyanzi) in the TRANSCEND NHL 001 trial (NCT02631044), and compared favorably with glofitamab monotherapy in a similarly refractory population. Part 3 of BP41072, a dose-expansion stage evaluating the regimens showing the most promise in part 2, is ongoing.

Reference

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