Epcore DLBCL-3 First Disclosure: Fixed-Duration Epcoritamab Monotherapy in Older (≥75 y), Anthracycline-Ineligible Patients with Previously Untreated Large B-Cell Lymphoma

Introduction: Low-dose rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-mini-CHOP) is a standard therapy for older patients (pts) with previously untreated (1L) diffuse large B-cell lymphoma (DLBCL). However, many pts are ineligible for anthracycline treatment (tx) due to advanced age, underlying comorbidities, and a high risk of cardiac toxicity. For these pts, various attenuated tx regimens have been evaluated; however, outcomes are suboptimal, and there remains an unmet need for effective, tolerable tx options. Epcoritamab SC, a CD3xCD20 bispecific antibody, has been approved as a single agent for the tx of different types of relapsed or refractory B-cell lymphomas, including DLBCL, after ≥2 lines of systemic therapy. EPCORE^® DLBCL-3 (NCT05660967) is a phase 2 trial evaluating epcoritamab as monotherapy or in combination with lenalidomide for anthracycline‑ineligible pts with newly diagnosed large B-cell lymphoma (LBCL). Here we report the first efficacy and safety results from the epcoritamab monotherapy arm of the study.

Methods: Elderly pts with 1L CD20⁺ LBCL who were ineligible for anthracycline-based tx due to age ≥80 y or age ≥75 y with underlying comorbidities were enrolled. In the epcoritamab monotherapy arm (arm A), pts received step-up doses of epcoritamab SC (0.16 mg on cycle [C] 1 day [D] 1 and 0.8 mg on C1D8) followed by epcoritamab 48 mg for a fixed duration of up to 1 y (28-d Cs; QW C1–3, Q4W C4–12). Cytokine release syndrome (CRS) prophylaxis with dexamethasone and adequate hydration was recommended during C1. The primary endpoint was complete response (CR) rate (percentage of pts with a best overall response of CR) per Lugano criteria.

Results: As of May 31, 2024 (median follow-up, 6.0 mo [95% CI, 5.1–8.0]), 45 pts were randomized to arm A (44 received epcoritamab monotherapy). Median age was 81 y (range, 77–95), 38% of pts were ≥85 y of age, 40% were male, 87% had cardiac and/or cardiovascular comorbidities, 29% had underlying nervous system disorders/neurocognitive impairment, 22% had underlying psychiatric disorders, 71% had significant renal impairment (moderate [CrCl 30 to <60 mL/min], 67%; severe [CrCl 15 to <30 mL/min], 4%), 93% had DLBCL, 53% had Ann Arbor stage IV disease, 29% had bulky disease (≥7 cm), and 58% had IPI ≥3. At the time of data cutoff, 4 pts (9%) had completed tx per protocol, 22 pts (50%) remained on tx, and 18 pts (41%) had discontinued epcoritamab tx, most commonly due to disease progression (n=10; 23%). Among response‑evaluable pts (n=39), overall response rate per investigator was 74% (29/39) and CR rate was 64% (25/39). Responses occurred early: median times to response and CR were 1.4 mo and 2.4 mo, respectively, with most pts having a response at their first assessment. At 6 mo, an estimated 84% of responders maintained a response, 88% of complete responders remained in CR, and 76% of all enrolled pts remained alive. Among 15 responders (14 with CR, 1 with partial response) evaluated for minimal residual disease (MRD), MRD negativity was observed in 93% (14/15; AVENIO assay, <1 mutant molecule per mL), with circulating tumor DNA decreased by 99.8% (median of 2.69 log-fold reduction) by C3D1. The most common (≥20% of pts) tx‑emergent AEs (TEAEs) were CRS (68%), fatigue (23%), and constipation (20%). Four fatal TEAEs (COVID-19, cytomegalovirus reactivation, tumor lysis syndrome, and tumor hemorrhage) occurred. Seven pts (16%) discontinued tx due to TEAEs (acute kidney injury, anemia and neutropenia, ataxia, fatigue, immune effector cell–associated neurotoxicity syndrome [ICANS], respiratory failure, and tumor lysis syndrome; n=1 each). CRS was primarily low grade (G; 36% G1, 27% G2, 5% G3) and resolved in 97% of pts; no CRS events led to tx discontinuation. ICANS events were reported in 7 pts (9% G1, 5% G2, 2% G3); 1 led to tx discontinuation. Of these 7 pts, all had neurocognitive impairment and/or decreased ICE scores at study entry.

Conclusions: In this difficult-to-treat, elderly pt population with numerous underlying comorbidities, treatment with single-agent epcoritamab resulted in high overall and complete response rates with a manageable safety profile. These results indicate that epcoritamab monotherapy is a promising tx option for frail pts with LBCL who are ineligible to receive anthracycline-based chemotherapy and support further evaluation of epcoritamab in this pt population.