Subcutaneous Epcoritamab in Combination with R-CHOP in Patients with Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma: Preliminary Results from a Phase 1/2 Trial
Authors: Belada David , Christensen Jacob Haaber , Drott Kristina , Snauwaert Sylvia , Brody Joshua , Narkhede Mayur , Offner Fritz , Elliot Brian , Liu Tracy , Cota Stirner Mariana , Abbas Aqeel , Falchi Lorenzo , Clausen Michael Roost 
Published: November 2021

Abstract
Background: In patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) that is considered high risk (revised International Prognostic Index [R-IPI]: 3-5), standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is associated with a 4-year overall survival rate of 55% (Sehn et al, Blood 2007). Epcoritamab (DuoBody ®-CD3×CD20) is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on malignant B cells to induce T-cell-mediated killing. Single-agent epcoritamab demonstrated a manageable safety profile and substantial antitumor activity in pts with heavily pretreated B-cell non-Hodgkin lymphoma (NHL) in the first-in-human phase 1/2 trial (EPCORE NHL-1; NCT03625037). Among pts with relapsed/refractory DLBCL treated at the identified recommended phase 2 dose (RP2D) of 48 mg (n=8), the overall response rate was 88% and the complete response rate was 38% (Hutchings, Lancet, in press). These encouraging data supported initiation of the EPCORE NHL-2 phase 1/2 trial (NCT04663347), which is evaluating epcoritamab in combination with various standard of care therapies in pts with B-cell NHL. We present data from arm 1 of this trial, in which epcoritamab in combination with R-CHOP is evaluated in pts with previously untreated high-risk DLBCL.
Methods: Adults with previously untreated DLBCL and an R-IPI score ≥3 received flat-dose epcoritamab in combination with standard R-CHOP for 6 cycles followed by epcoritamab monotherapy. The study includes a dose-escalation cohort (epcoritamab doses: dose level 1 = 24 mg; dose level 2 = 48 mg). Step-up dosing of epcoritamab (ie, priming and intermediate doses before first full dose) and corticosteroid prophylaxis were used as previously described (Hutchings, Lancet, in press) to mitigate cytokine release syndrome (CRS). Tumor response was evaluated by positron emission tomography-computed tomography obtained once every 6 weeks for the first 24 weeks.
Results: As of July 15, 2021, 9 pts have been treated with the combination of epcoritamab + R-CHOP (4 with epcoritamab 24 mg; 5 with 48 mg). Median age was 66 years (range, 56-78). All pts had stage III-IV disease. At data cutoff, all pts remained on treatment with a median follow-up of 12.2 weeks (range, 2.2-28.2). The most common treatment-emergent adverse events were CRS (56%; all grade 1/2), anemia (56%; grade 1-3), neutropenia (44%; all grade 3/4), fatigue (33%; all grade 1/2), and peripheral neuropathy (33%; all grade 1/2). Notably, no grade ≥3 CRS events or cases of febrile neutropenia were reported. No dose-limiting toxicities have been observed. Four pts have had ≥1 response assessment, with 3 achieving complete metabolic response (CMR; all in the epcoritamab 24 mg dose-escalation cohort) and 1 pt achieving partial metabolic response (epcoritamab 48 mg cohort) by week 6; 2 of the 3 pts with CMR had response assessments at 6 months, and both remained in CMR at that time. Both dose cohorts have been cleared by the Dose Escalation Committee and Safety Committee, and the expansion part has been opened to enroll additional pts.
Conclusions: These preliminary data from a small number of pts suggest that epcoritamab in combination with R-CHOP has a manageable safety profile with no new safety signals. Adverse events were similar to those previously reported for epcoritamab and R-CHOP individually. All evaluable pts achieved early responses, and all pts remain on treatment. Updated and additional data from pts treated in the expansion phase will be presented. These findings warrant further evaluation of epcoritamab for the treatment of high-risk, newly diagnosed DLBCL.

Disclosures
Belada: Genmab: Research Funding. Drott: Roche: Honoraria; Kyowa Kirin: Honoraria; Respiratorius AB: Membership on an entity's Board of Directors or advisory committees. Narkhede: TG Therapeautics: Research Funding; Genmab: Other: Medical writing support, Research Funding; Genentech/Roche: Research Funding; Gilead: Research Funding. Elliot: Genmab: Current Employment, Patents & Royalties: P158-US-PSP3 . Liu: Genmab: Current Employment. Cota Stirner: AbbVie: Current Employment. Abbas: Genmab: Current Employment. Falchi: Abbvie: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.