Subcutaneous Epcoritamab in Novel Combinations with Antineoplastic Agents Among Patients with B-Cell Non-Hodgkin Lymphoma in a Phase 1b/2, Multicenter, Open-Label Study: Assessing Safety, Tolerability, and Preliminary Efficacy (EPCORE NHL-5)

Background: Novel treatment options for patients with B-cell non-Hodgkin lymphoma (B-NHL) are encouraging. Epcoritamab is a subcutaneously administered, bispecific antibody that binds to CD3⁺ T cells and CD20⁺ B cells, inducing T cells to kill CD20⁺ tumor cells through a unique mechanism of action (MOA). Clinically meaningful and compelling efficacy with epcoritamab was seen among patients with relapsed or refractory (R/R) B-NHL in the phase 1/2 EPCORE NHL-1 (NCT03625037) trial, including deep and durable responses (overall response rate [ORR], 63%; complete response [CR] rate, 39%; median duration of response [DOR], 12 months) in a population with highly refractory large B-cell lymphoma with a manageable safety profile (n = 157) (Thieblemont et al, EHA 2022). Investigations of agents such as polatuzumab vedotin, tafasitamab in combination with lenalidomide, and ibrutinib have shown promise in diffuse large B-cell lymphoma (DLBCL) (Goy et al, Blood 2019; Salles et al, Lancet Oncol 2020; Tilly et al, N Engl J Med 2022). Combining epcoritamab with antineoplastic agents that have different MOAs may offer enhanced clinical benefit to patients with B-NHL. The aims of this study (EPCORE NHL-5; NCT05283720) are to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy of epcoritamab and determine the recommended dose of epcoritamab when coadministered with other antineoplastic agents as novel combinations in patients with B-NHL. This open-label, global, multicenter study will evaluate epcoritamab in novel combinations with antineoplastic agents in 3 arms (arm 1: epcoritamab plus lenalidomide in R/R DLBCL; arm 2: epcoritamab, ibrutinib, and lenalidomide in R/R DLBCL [post-chimeric antigen receptor T-cell (CAR T) therapy]; arm 3: epcoritamab plus pola-R-CHP in treatment-naive DLBCL).

Study Design and Methods: Each arm includes a dose-escalation/-expansion phase. The primary endpoint is dose-limiting toxicities. Secondary endpoints include best overall response, CR, DOR, progression-free survival, time to response, and overall survival. Additional endpoints are patient-reported outcomes, safety, pharmacokinetics, immunogenicity, and disease- and/or drug-related biomarkers. Patients must be at least 18 years of age with an Eastern Cooperative Oncology Group performance status of 0 to 2. Other inclusion criteria are measurable disease by positron emission tomography/computed tomography and diagnosis of CD20⁺ non-Hodgkin lymphoma, including DLBCL, DLBCL not otherwise specified, "double-/triple-hit" DLBCL, and grade 3B follicular lymphoma; other indications are being considered for additional novel combinations. Patients must not have prior therapy with epcoritamab or other bispecific antibodies targeting CD3 and CD20 and no autologous stem cell transplant within 3 months of screening. Enrollment is ongoing and planned in North America, Europe, and Asia.

Sehn:Chugai: Consultancy, Honoraria; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Honoraria; Teva, Roche/Genentech: Consultancy, Honoraria, Research Funding; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Debiopharm, Genmab, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Novartis, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Consultancy. Duell:MorphoSys: Consultancy, Research Funding; Incyte: Consultancy; Regeneron: Research Funding. Avivi:Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Brody:Seagen: Consultancy; Epizyme: Consultancy; Gilead/Kite: Research Funding; BMS: Research Funding; Genentech: Research Funding; ADC Therapeutics: Consultancy; Merck: Research Funding; SeaGen, Roche, Genentech, Merck, ADC Therapeutics, Epizyme, Gilead, Kite, Astrazeneca: Research Funding. Yoon:Novartis: Honoraria; BMS: Honoraria; Amgen: Honoraria; Roche: Honoraria; Kirin Pharm: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Celltrion: Honoraria, Research Funding; Sanofi: Research Funding; Beigene: Research Funding; Boryung pharmaceutical: Honoraria, Research Funding; SAMYANG Biopharm: Honoraria, Research Funding; Pharos iBio: Consultancy; Ab clone: Consultancy; GI cell: Consultancy; Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; GC Cell: Consultancy; AbbVie: Research Funding. Elliot:Genmab: Current Employment, Current equity holder in publicly-traded company. Siddani:AbbVie: Current Employment, Current equity holder in publicly-traded company. Bai:AbbVie: Current Employment, Current equity holder in publicly-traded company. Parikh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Seliem:AbbVie: Current Employment, Current equity holder in publicly-traded company. Dinh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Skarbnik:TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Genmab: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria.