Introduction:

Patients (pts) with R/R DLBCL ineligible for chimeric antigen receptor T cell (CAR T) therapy or autologous stem cell transplant (ASCT) have limited treatment (tx) options and poor outcomes. In R/R DLBCL, standard salvage therapy with gemcitabine plus oxaliplatin (GemOx) yielded a complete response (CR) rate of 25%, overall response rate (ORR) of 41%, median progression-free survival (mPFS) of 3.6 mo, and median overall survival (mOS) of 12.9 mo (Abramson JS, et al. Lancet 2024;404:1940–1954). In the EPCORE® NHL-2 trial (NCT04663347), epcoritamab (epcor), a CD3×CD20 bispecific antibody, combined with GemOx led to high response rates in pts with R/R DLBCL ineligible for ASCT. Here, we report long-term durability data from this cohort after >2 y of follow-up.

Methods: Pts with CD20+ R/R LBCL ineligible for ASCT due to advanced age, performance status, or lack of response to prior ASCT received subcutaneous epcor (step-up doses: 0.16 mg, 0.8 mg; 48 mg thereafter) QW in cycles (C) 1–3, Q2W in C4–9, and Q4W in ≥C10. GemOx (gemcitabine 1000 mg/m², oxaliplatin 100 mg/m²) was given Q2W for 4 C (8 total doses). The primary endpoint was ORR by Lugano criteria. Minimal residual disease (MRD) negativity was assessed as a secondary endpoint, using the exploratory AVENIO Oncology circulating tumor DNA (ctDNA) method (cutoff: <1 mutant molecule per mL). Data cutoff was April 9, 2025; efficacy assessments were per investigator.

Results: In total, 103 pts were treated. Median age was 72 y (range, 20–87). The pt population was 76% White, 4% Black/African American, and 4% Asian; pts were enrolled across the United States (US; 27%), Europe (72%), and Australia (1%). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 37% had 1 pLOT; 61% had Ann Arbor stage IV, 7/66 (11%) assessed pts had double-hit/triple-hit disease, 33% had bulky disease (≥7 cm), 52% had primary refractory disease, 70% were refractory to last therapy, 10% had prior ASCT, and 28% had prior CAR T therapy.

ORR was 81%, and 60% of pts had a CR. After a median follow-up of 27.9 mo (range, 1.0+ to 47.9), epcor + GemOx led to mPFS of 16.3 mo (95% CI, 8.3–not reached [NR]), and mOS of 28.2 mo (95% CI, 11.7–NR). At 2 y, an estimated 48% of all pts were progression-free and 53% were alive. Responses were durable, with a median duration of response of 27.3 mo (95% CI, 11.7–NR), and a median duration of complete response (mDOCR) of 40.7 mo (95% CI, 40.7–NR). An estimated 67% of complete responders remained in CR at 2 y. Among pts with 1 pLOT, CR rate was 74% and mDOCR was NR. Pts with >1 pLOT (some received up to 6 pLOTs) experienced clinically meaningful responses (CR rate: 52%), with mDOCR of 40.7 mo (95% CI, 17.5–NR). When analyzed by region, outcomes were consistent in pts from the US and Europe. Overall MRD negativity by C7 day 1 (D1), was observed in 71% (44/62) of MRD-evaluable pts. Deep and sustained MRD negativity through C7D1 was observed across difficult-to-treat subgroups.

At data cutoff, 24% (25/103) of pts remained on tx. There were 16 pts who discontinued tx while in CR for reasons other than progressive disease or death; 12 (75%) of these pts remained in CR (median time since end of tx, 8.8 mo [range, 0.5–26.8]) at data cutoff.

Safety was consistent with previous reports (Brody JD, et al. Blood 2025;145:1621–1631). Incidence of serious infections was highest (23%) in the first 24 weeks of tx, as expected, given known toxicities of the individual components, then decreased and remained consistent over time. With 14.7 mo more follow-up since the last report, 4 additional pts had an infection, and 4 additional pts experienced grade 5 treatment-emergent adverse events (pancreatic adenocarcinoma, lung infection, subacute sclerosing panencephalitis, COVID-19).

Conclusions:

Epcor + GemOx demonstrated sustained remissions of >2 y, prolonged PFS and OS, and deep MRD negativity in challenging-to-treat 2L+ R/R DLBCL; these results are widely applicable to a diverse pt population across the US and Europe. With longer follow-up, the safety profile remained consistent with previous reports. These findings support the combinability of epcor with standard-of-care chemotherapy and offer an effective option for ASCT-ineligible pts, a population with otherwise limited tx choices.

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2025
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