High-Risk Features Linked to Early Progression on Epcoritamab/Glofitamab

A prospective cohort study presented at the 2025 ASH Annual Meeting & Exposition found that most disease progression in patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with single-agent epcoritamab-bysp (Epkinly) or glofitamab-gxbm (Columvi) occurred soon after starting treatment. Notably, almost half of these patients who progressed did not go on to receive any subsequent therapy.¹

The overall response rate (ORR) among 271 evaluable patients was 54%, with a 33% complete response (CR) rate. Median progression-free survival (PFS) was 2.5 months, and overall survival (OS) was 7.7 months. Median time to progression after initiation of bispecific antibodies was 1.5 months.

“Compared to pivotal trials, epcoritamab and glofitamab continue to be applied in a broad population of patients with high-risk large B-cell lymphoma,” said Taylor R. Brooks, MD, a lymphoma specialist at the Cleveland Clinic in Cleveland, Ohio, who presented these data. “Salvage therapies following progression are heterogeneous, and response rates are low with poor survival.”

Progressive disease was the most common cause of death (82.6%), followed by infection (13.8%). Cytokine release syndrome (CRS; n = 4), immune effector cell–associated neurotoxicity syndrome (ICANS; n = 2), and secondary malignancy (2.6%) comprised other deaths in the cohort.

Deaths due to progressive disease or infection occurred earlier in patient treatment, with the majority occurring within 6 months of treatment initiation. Beyond 6 months, additional infection-related mortalities were associated with Aspergillus pneumonia (n = 1), COVID-19 (n = 2), fungemia (n = 1), and bacteremia (n = 2).

Of late deaths, 1 occurred on therapy, 2 occurred after completion of glofitamab, and 1 occurred after allogeneic transplantation.

Median duration of CR was 20 months for patients treated with epcoritamab and 18 months for patients treated with glofitamab, and partial response (PR) rates in these groups were 3.1 months and 3.9 months, respectively.

Patients in epcoritamab and glofitamab received medians of 5 and 2 cycles, respectively. Patients with stable or progressive disease as best response received a similar number of cycles, regardless of which bispecific antibody they received, but those who achieved partial response (PR) or CR varied in number of cycles by treatment.

In PR and CR groups, few patients were treated with over 12 cycles of glofitamab. Some of those achieving response with epcoritamab received continuous dosing.

What Factors Made Patients More Likely to Progress on BsAb Therapies?

The REALBiTE study was initiated in 2023, involving 21 academic centers treating patients with relapsed/refractory LBCL with single-agent epcoritamab or glofitamab.

In total, 189 patients progressed on therapy, and 139 did not. Malignancy type was shown to have a statistically significant association with progressor status, with double-hit lymphoma (DHL)/triple-hit lymphoma (THL) comprising 19.6% of progressors vs 11.5% of non-progressors (P = .033).

Of note, IPI status over 2 at treatment initiation was associated with disease progression, with 70.6% in the progressor group having this status vs 55.0% in the non-progressor group (P = .006). ECOG status of 2 or higher was also associated with a significant 36.5% of progressors compared with 20.0% of non-progressors (P = .002).

Further, primary refractory disease (58.3% vs 40.7%, respectively; P = .004), refraction to last line of therapy before bispecific antibody (84.2% vs 67.0%; P = .003), and undetectable CD20 by IHC prior to bispecific antibody (13.2% vs 3.0%; P = .036) were also linked with significantly higher rates of progression vs non-progression.

Salvage and Consolidation Therapies After Epcoritamab or Glofitamab

First salvage therapies following treatment with epcoritamab or glofitamab included chemo(immune)therapy (25%); loncastuximab tesirine (Zynlonta;18.5%); local therapy (13.9%); tafasitamab-cxix (Monjuvi) with or without lenalidomide (Revlimid; 9.3%); CAR T-cell therapy (6.5%); polatuzumab vedotin (Polivy) with or without rituximab (Rituxan), cyclophosphamide, doxorubicin (Adriamycin), and prednisone (R-CHP; 5.6%); brentuximab vedotin (Adcetris) with or without lenalidomide (5.6%); clinical trial (4.6%); other (3.7%); rituximab with or without lenalidomide (2.8%); selinexor (Xpovio; 1.9%); checkpoint inhibitor (1.9%); and allogeneic hepatocellular transplant (0.9%). ORRs for the first 8 of respective salvage therapies were 33%, 17%, 60%, 20%, 43%, 40%, 50%, and 20%.

Brooks noted that local therapies were mostly radiation and that all of those who responded to CAR T-cell salvage therapy achieved CR. Of those who received subsequent therapy, 56% had disease progression.

With a median follow-up of 12 months for those for whom survival and treatment data were available, median PFS and OS from time of first salvage were 1.9 months and 4.3 months, respectively (P <.0001); the 12-month survival rate was 19.5%.

“One particularly notable subgroup includes patients treated with epcoritamab or glofitamab who subsequently went on to receive allogeneic hematopoietic progenitor cell transplantation,” noted Brooks.

He emphasized that 12 patients received allogeneic hematopoietic cell transplantation as response consolidation; 5 were as a consolidation of CR, 6 were as consolidation of PR, and 1 had three additional lines of post-bispecific therapy salvage. Median age for these patients was 5 years, and 8 maintained PFS at 9 months of follow-up.

Twenty-three patients went on to receive CAR T-cell therapy following bispecific antibodies. These included 8 receiving consolidation therapy (CR, 3; PR, 5) and 14 receiving salvage therapy. Patients receiving consolidation CAR T-cell therapy had a median of 4 cycles (range, 0-7) of bispecifics.

The ORR for those who received CAR T-cell therapy after bispecifics was 43.5%, with the majority achieving CR, with similar response rates regardless of use as consolidation or salvage therapy.

“Outcomes appear favorable for responders,” said Brooks in his presentation. “How we might predict these favorable outcomes remains an open question.”

Further Patients Characteristics

More patients in each group received epcoritamab (64.6% and 57.6%, respectively) vs glofitamab (35.4%; 42.4%; P = .208). Most patients in progressor (69.3%) and non-progressor (61.9%) groups did not have a history of indolent non-Hodgkin lymphoma (P = .314).

Most patients in progression (57.7%) and non-progression (55.4%; P = .735) groups had prior CAR T-cell therapy, and of those, 66.1% of progressors and 52.6% of non-progressors were refractory to CAR T-cell therapy (P = .071).

Ann Arbor stage III/IV disease was more common in both responder and non-responder groups (86.8% and 81.3%, respectively; P = .217), as was non-bulky disease (73.8% and 83.2%; P = .057).

More patients in responder (68.8%) and non-responder (59.7%) groups were male (P = .101), and the median age at treatment initiation was 68.0 years (IQR, 60.0-76.0) in the progressor group vs 69.0 years (IQR, 63.0-78.0) in the non-progressor group (P = .163).

Study Background

Prior findings from the REALBiTE cohort published in October 2025 demonstrated that at a follow-up of just over 6 months, patients had a higher rate of advanced-stage disease, lower performance status, and comorbidities that would have excluded 71% from trials for these therapies.²

While response rates identified in this study were consistent with pivotal trials, PFS and OS were lower in these patients, indicating a shorter response time for real-world patient populations. At a median follow-up of 14.6 months, findings presented at the ASH meeting, which included an additional 100 patients, were consistent with prior REALBiTE survival data.^1,2

Disclosure: Brooks received research funding from Genmab.

REFERENCES

1.Brooks T, Mian A, Nedved A, et al. Outcomes following disease progression after epcoritamab or glofitamab in the real-world outcomes of bispecific T-cell engagers (REALBiTE) multi-center, retrospective cohort study. Blood. 2025;146(suppl 1):402. doi:10.1182/blood-2025-402

2.Brooks T, Zabor EC, Bedelu YB, et al. Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab. Blood. 2025;146(18):2177-2188. doi:10.1182/blood-2025029117