Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma after ≥2 lines of systemic therapy based on results from the phase 1/2 EPCORE® NHL-1 trial (NCT03625037). Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is an accepted standard treatment for patients with previously untreated (1L) DLBCL; however, relapse rates can reach 40%. High-risk patients with International Prognostic Index (IPI) 3-5 and patients with double-hit/triple-hit lymphoma have suboptimal complete response (CR) rates and long-term outcomes. Following R-CHOP, 5-y estimates of progression-free/overall survival (OS) decreased from 81%/88% in patients with IPI 0-1 to 67%/76% for IPI 2, 58%/67% for IPI 3, and 46%/54% for IPI 4-5 (Ruppert et al, Blood 2020), suggesting a need for novel regimens to increase cure rates for newly diagnosed patients with DLBCL with high-risk features. Previously, in arm 1 of the EPCORE NHL-2 trial (phase 1b/2; NCT04663347), the combination of epcoritamab + R-CHOP showed encouraging response rates and a manageable safety profile in 1L DLBCL, including in high-risk patients (Clausen et al, EHA 2023). Here, we present long-term follow-up beyond 2 y, including in subgroups, and minimal residual disease (MRD) analyses for the first time.

Methods: Adults with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (QW in cycles 1-4; Q3W in cycles 5-6) + R-CHOP for 6 cycles (21 d each) followed by epcoritamab monotherapy Q4W in 28-d cycles for up to 1 y. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint using the exploratory AVENIO ctDNA method. Double-hit/triple-hit status was assessed by central lab.

Results: As of May 15, 2024, 47 patients had received epcoritamab 48 mg + R-CHOP, with a median follow-up of 27.4 mo (range, 0.8-33.9). All patients had IPI 3-5 at screening, 6 (21%) of 28 patients with evaluable tissue available had double-hit/triple-hit DLBCL, and 16 patients (34%) had bulky disease (>10 cm). The median time from diagnosis to first dose was 4 wk (range, 1.3-60.4). Median relative dose intensity for all R-CHOP components was ≥95%.

Among 46 evaluable patients, the ORR was 100%, with a CR rate of 87%. Most patients (96%; 44/46) completed 6 cycles of R-CHOP; 91% (40/44) had a CR, and the 2 patients who did not complete 6 cycles of R-CHOP had a partial response. Notably, patients with double-hit/triple-hit DLBCL had a CR rate (83%; 5/6) similar to the overall population. An estimated 74%/87% of patients remained progression free/alive at 24 mo. Durable responses were observed, with an estimated 83% of patients with CR remaining in CR at 24 mo. MRD negativity (cutoff, <1 mutant molecule per mL) was observed in 91% of evaluable patients (30/33).

The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (70%), anemia (68%), CRS (60%), fatigue (49%), nausea (47%), pyrexia (43%), and injection-site reaction (40%). Four patients (9%) discontinued epcoritamab due to TEAEs; G5 TEAEs occurred in 2 patients (COVID-19 and septic shock). CRS events were mostly low grade (45% G1, 11% G2, 4% G3) and mainly occurred after the first full dose; all resolved, and none led to discontinuation. ICANS occurred in 2 patients (G1, n=1; G2, n=1) and resolved in a median of 2.5 d without leading to discontinuation.

Conclusions: Fixed-duration epcoritamab + R-CHOP induced deep, durable CRs (24-mo estimated duration of CR, 83%) and high rates of MRD negativity (91% of evaluable patients), leading to long-term remissions (24-mo estimated OS, 87%) beyond 2 y in patients with 1L DLBCL, including those with high-risk features, such as double-hit/triple-hit disease. These results suggest a high curative potential for this potent first-line combination. The safety profile was manageable, with no new safety signals detected, underscoring the combinability of epcoritamab with standards of care in 1L DLBCL. These data compare favorably with R-CHOP alone in this setting and further support the ongoing phase 3 trial of epcoritamab + R-CHOP in 1L DLBCL(NCT05578976).

Disclosures

Falchi:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Genentech, ADC Therapeutics, Seagen, Ipsen: Membership on an entity's Board of Directors or advisory committees; Taylor Francis: Other: Journal Editor; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EvolveImmune: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Roche: Consultancy, Research Funding; Genentech, Roche, Genmab, AbbVie, Innate, BeiGene: Research Funding; Genentech, Roche, Genmab, Abbvie, Sanofi, EvolveImmune: Honoraria; Genmab: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kaplan: Other: CME Presentation: Projects in Knowledge. Cordoba:Takeda: Consultancy, Speakers Bureau; Genmab: Consultancy; BMS: Consultancy, Speakers Bureau; Kite: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Kyowa Kirin: Consultancy; Pfizer: Research Funding. Linton:Nurix: Research Funding; CellCentric: Research Funding; Genmab: Consultancy, Other: Member of the Epcoritamab Global Council, Research Funding; AbbVie: Consultancy, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Janssen: Research Funding; BeiGene: Consultancy, Research Funding; MSD: Research Funding; AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Roche: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; BMS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Regeneron: Research Funding; Step Pharma: Research Funding; Viracta: Research Funding; Celgene: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Clausen:Pfizer: Other: Travel Expenses; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Other: Travel Expenses; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel Expenses. Oki:AbbVie: Current Employment. Steele:Genmab: Current Employment, Other: owns Genmab stock; Janssen: Other: owns Janssen stock; AbbVie: Other: owns AbbVie stock. Hao:Genmab: Current Employment. Archer:Genmab: Current Employment. Rana:Genmab: Current Employment. Belada:Takeda: Consultancy, Research Funding; Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy; AbbVie: Consultancy; Swixx BioPharma: Consultancy; Astra Zenecca: Research Funding; Regeneron: Research Funding; MorphoSys: Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy; Pharmacyclis: Research Funding; Swixx: Consultancy.

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2024
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