Abstract Introduction: Epcoritamab (epco) is a bispecific antibody (BsAb) that is FDA approved for patients (pts) with R/R LBCLs based on the results of the pivotal EPCORE NHL-1 clinical trial. There are limited real-world datasets that report on outcomes and safety compared to trial settings. This study examines the association of clinical and disease characteristics with survival outcomes in pts with R/R LBCLs treated with epco in a real world pt cohort. Methods This is a multicenter retrospective study of adult pts with R/R LBCL who received epco outside of a clinical trial between 2023 and 2025 at 11 centers in the Collaborative US Bispecifics Consortium (CUBIC). Trial eligibility was determined using the inclusion criteria in EPCORE NHL-1. Efficacy outcomes included overall response rate (ORR), complete response rate (CRR), progression free survival (PFS) and overall survival (OS). PFS/OS were calculated from date of first epco dose and analyzed using the Kaplan Meier method. Results A total of 142 pts with LBCL were included, including 83% (n=118) with DLBCL, NOS, 13% (n=19) with high grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements (DH) or HGBCL, NOS and 28% (n=39) with transformed indolent lymphoma (n=27) or CLL (n=12). Prior to BsAb therapy, median age was 70 years (range 22-93), 68% were male (n=96), median number of prior lines of therapy (pLOT) was 3 (range 1-11), 91% pts had stage IV disease (n=108), 30% had ECOG performance status (PS) of ≥ 2 (n=39), 84% had extranodal (EN) disease (n=102), and 53% with ≥2 EN sites. 80% of pts were refractory to their pLOT and 59% had prior CAR-T. 67 (47%) were trial-ineligible, 52 (36%) due to cytopenias. Of 138 pts with complete safety data, 46 pts (33%) had a cytokine release syndrome (CRS) event (grade (G)1-2, 29%; G3, 3.5%, G5 0.7%,concurrent severe COVID infection at time of 3rd dose) and 17 (12%) had an immune effector cell-associated neurotoxicity syndrome (ICANS) event (G1, 6.5%; G2, 4.3%, G3, 0.7%). 38% of pts had an infection during epco and 18% required an ICU stay for an adverse event (AE). Among all pts, the ORR was 48.7% (95% CI: 39.4-58.1%) and the CRR was 30.8% (95% CI: 22-40%). The median time to best response was 2.3 months (mo)(IQR 1.8-6.3 mo). At a median follow up of 13.9 mo (n=142), the median PFS was 3.6 mo (95% CI: 2.0-4.6 mo) and median OS was 6.2 mo (95% CI: 4.7 -10.5 mo). 1-year PFS and OS were 26.8% (95% CI: 20-36%) and 37.2% (95% CI: 29-47%), respectively. 56% discontinued due to disease progression. Trial ineligible pts had significantly inferior ORR and CRR compared to trial eligible pts (ORR of 37.3% vs 57.6%, p=0.04; CRR of 19.6% vs 39.4%, p=0.02). Median PFS was 1.6 mo and 4.6 mo in trial ineligible and eligible pts, respectively (p=0.001). Median OS was 4.7 mo and 10.5 mo for trial ineligible and eligible pts, respectively (p=0.008). Trial eligibility was not associated with an increased risk of CRS (p=0.7), ICANS (p=1.0), infections (p=0.46), or ICU stay (p=0.07). There was no difference in ORR, CRR, PFS or OS among pts by age (65), gender, race, cell-of-origin status (by IHC), presence of double expressor, DH, bulky disease, pLOT (3 vs ≥4) or prior CAR-T. Pre-BsAb high risk IPI (4-5), presence of B symptoms, elevated LDH, stage III/IV, ≥2 EN sites, ECOG PS of ≥ 2, and refractory to pLOT were associated with both inferior PFS and OS. Multivariate cox regression analysis demonstrated that disease refractory to the pLOT (HR 1.9, p=0.02), elevated LDH (HR 1.8, p=0.01) and ECOG PS ≥ 2 (HR 1.5, p=0.05) were associated with inferior PFS and OS (pLOT HR 2.1, p=0.02; LDH HR 2.2, p=0.004; ECOG PS HR 1.8, p=0.01). Conclusions In this analysis of the largest real-world cohort of pts treated with epco, inferior survival outcomes were identified in trial ineligible pts while trial eligible pts demonstrated similar outcomes as the pivotal epco trial. Pts with clinical features correlating to a higher disease burden (elevated LDH, B symptoms, stage III/IV, EN sites), disease refractory to last pLOT and poor ECOG PS had inferior survival outcomes, however DH histology, a subgroup associated with worse survival outcomes, did not. Trial ineligible pts did not have an increased risk of key AEs (CRS, ICANS, ICU stay), but among all pts we observed a high rate of ICU admission, lower rate of any grade CRS but a higher rate of ≥ G3 events (4.7%), and a higher rate of ICANS compared to the pivotal trials and other real-world studies.
Bock et al. (Mon,) studied this question.