Prior Bendamustine (Benda) Exposure Did Not Impact Clinical Outcomes and Decreased CD4+ but Not CD8+ T-Cells in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with the Bispecific Antibody Epcoritamab (Epcor)

Background: Prior treatment with benda, depending on the time from last dose, has been shown to negatively impact T-cell fitness and clinical outcomes in patients receiving chimeric antigen receptor T-cell (CAR T) therapy for relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (Iacoboni et al, JCO 2024). Bispecific T-cell–engaging antibodies share a similar mechanism with CAR T therapies, raising concerns regarding efficacy after treatment with benda. Epcor, a subcutaneous CD3×CD20 bispecific antibody, is approved for adults with R/R large B-cell and follicular lymphomas after ≥2 lines of systemic therapy. Here we evaluate the efficacy, safety, and T-cell phenotypes in patients with R/R DLBCL with and without prior benda exposure from the phase 1/2, nonrandomized, open-label, global EPCORE NHL-1 study (NCT03625037).

Methods: Eligible patients were adults with CD20+ R/R DLBCL with an Eastern Cooperative Oncology Group performance status 0–2, de novo or transformed from an indolent subtype, ≥2 lines of prior systemic anti-neoplastic therapy including ≥1 anti-CD20 monoclonal antibody, and ineligible for or experienced treatment failure with autologous stem cell transplant. Patients received subcutaneous epcor weekly in cycles 1–3, every 2 weeks in cycles 4–9, and every 4 weeks in cycle ≥10; each cycle was 28 days. Epcor was administered using two step-up dosing in cycle 1: priming (0.16 mg) and intermediate doses (0.8 mg) followed by 48-mg full doses. Endpoints included independent review committee–assessed overall response rate (ORR) per Lugano 2014 criteria, progression-free survival (PFS), overall survival (OS), and safety, including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Flow cytometry was performed on blood samples collected at baseline.

Results: As of April 23, 2023, 37 of 139 enrolled patients with DLBCL had previously been treated with benda at any time and 102 had no prior benda. Median duration of epcor treatment was 3.5 months (range: 0.3–29.7; median cycles: 4) and 4.2 months (range: 0.03–31.7; median cycles: 5) in patients with and without prior benda, respectively. There was no difference in response rates between groups: ORR was 59.5% (95% CI: 42.1, 75.2; complete response [CR]: 43.2%, partial response [PR]: 16.2%) and 62.7% (95% CI: 52.6, 72.1; CR: 39.2%, PR: 23.5%), in patients with or without prior benda, respectively. Median PFS was 4.4 months (95% CI: 2.6, 16.7) with 22.5 months of follow-up in patients with prior benda and 4.4 months (95% CI: 3.3, 11.0) with 22.3 months of follow-up in patients without prior benda. Median OS was 12.2 months (95% CI: 6.1, not reached) with 24.8 months of follow-up in patients with prior benda and 20.0 months (95% CI: 12.8, 27.8) with 25.8 months of follow-up in patients without prior benda. When comparing patients with and without prior benda exposure, similar rates of CRS (n=18, 48.6% vs n=51, 50.0%) and ICANS (n=2, 5.4% vs n=7, 6.9%) were observed. In addition, there were no statistical differences in response or survival in patients with benda as their last line of therapy vs those with no prior benda. Benda-exposed patients had lower T-cell counts at baseline (median 556, 349, and 671 cells/µL for benda-exposed, n=30, benda-exposed within 12 month from epcor, n=18, and benda naive, n=87). Baseline CD4+ T-cell counts were significantly lower in benda-exposed patients within 12 months of epcor vs benda-naive patients (P<0.001), but CD8+ T-cell counts were less impacted by benda (P=0.56). Analysis of T-cell markers showed a significantly higher proportion of PD-1+ and HLA-DR+ in CD4+ T cells (P<0.001) but no significant difference in the proportion of these markers in CD8+ T cells in benda-exposed patients within 12 months from epcor vs benda-naive patients (P=0.18 and P=0.2 for PD-1+ and HLA-DR+, respectively).

Conclusion: From this subanalysis of EPCORE NHL-1, efficacy and safety were similar to those of the main study findings regardless of benda exposure, demonstrating that prior benda exposure did not negatively affect epcor activity. Consistent with prior studies, benda caused a selective CD4+ T-lymphopenia and increased PD-1/HLA-DR expression whereas CD8+ cells remained relatively unaffected, suggesting limited effect on cytotoxic T cells. These data support the use of epcor in both benda-exposed and benda-naive patients.