Introduction: Relapsed or refractory (R/R) large B-cell lymphoma (LBCL) is challenging to treat; there remains a need for more effective treatment options for patients with third-line or later (3L+) LBCL. Epcoritamab is a subcutaneous CD3×CD20 bispecific antibody approved for the treatment of adults with R/R LBCL or R/R follicular lymphoma (FL) after ≥2 lines of systemic therapy, based on outcomes from the pivotal phase 2 EPCORE® NHL-1 trial (NCT03625037), in which epcoritamab monotherapy led to high complete response (CR) rates and deep, durable responses with manageable safety in patients with R/R LBCL. Pivotal results have been reported previously (Vose JM, et al. Blood 2024;144[Suppl 1]:4480). Here, we report updated data with an extended follow-up of over 4 years.

Methods: Adults with R/R CD20+ LBCL (including diffuse LBCL, high-grade B-cell lymphoma, primary mediastinal LBCL, and FL grade [G] 3B) and ≥2 prior lines of systemic therapy were treated with subcutaneous epcoritamab (0.16 mg and 0.8 mg step-up doses followed by 48-mg full doses) in 28-day cycles according to the approved dosing schedule: QW, cycles 1–3; Q2W, cycles 4–9; Q4W, cycles ≥10, until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate per Lugano criteria. Efficacy results presented here are based on investigators' assessment. The data cutoff date was May 2, 2025.

Results: Overall, 157 patients with R/R LBCL received epcoritamab monotherapy in the study. Median age was 64 years and 31% had bulky disease (>7 cm). Patients were heavily pretreated, with a median number of 3 prior lines of therapy (range, 2–11); 61% had primary refractory disease and 39% had received prior chimeric antigen receptor T cell therapy.

Median follow-up was 49.2 months (range, 0.3–57.0). In total, 59% (92/157) of patients achieved a response with epcoritamab monotherapy, including 41% (65/157) of patients who had a CR. At data cutoff, 42% (27/65) of CRs were ongoing. The overall median duration of CR was 37.7 months (95% confidence interval [CI], 25.1 to not reached), and the longest ongoing CR at the time of data cutoff was 54.5 months. Only 7 patients with a CR progressed after the first year: 5 progressed in years 1–2 and 2 progressed in years 2–3. Median OS in all patients was 18.5 months (95% CI, 11.7–27.7). At the 4-year landmark, an estimated 32% of all patients and 57% of patients with a CR remained alive. Patients remained on treatment for a mean of 11.8 months. The longest duration of therapy at data cutoff was 54.8 months.

Between 3–4 years, few patients had an AEs; 18 patients were on treatment during this time period. Since the last data cutoff, which had a median follow-up of 37.1 months (Vose JM, et al. Blood 2024;144[Suppl 1]:4480), 5 patients experienced a serious AE (grade 1 back pain, grade 3 urinary tract infection, grade 3 pneumonia, grade 3 syncope, grade 5 COVID-19). In addition, 1 patient discontinued treatment due to grade 2 bronchitis.

Conclusions: With more than 4 years of follow-up, epcoritamab monotherapy continues to demonstrate deep and durable remissions. Nearly half (42%) of all complete responders remained in remission after more than 4 years of median follow-up and 57% remained alive, demonstrating the potential for long-term disease-free survival with epcoritamab in this population with difficult-to-treat LBCL. The consistent safety profile and prolonged survival benefit highlight epcoritamab as a favorable chemotherapy-free, readily available treatment option in the 3L+ LBCL treatment setting.

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2025
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