Fixed-Duration Epcoritamab in Combination with Bendamustine + Rituximab for First-Line Treatment of Follicular Lymphoma: Initial Results from Epcore NHL-2 Arm 3

Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the treatment (tx) of relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma (FL) after ≥2 lines of systemic tx based on the phase 1/2 EPCORE® NHL-1 trial (NCT03625037). Bendamustine + rituximab (BR) is one of the most common first-line FL regimens (overall response rate [ORR], >99%; complete response [CR] rate, 30%; Flinn et al, Blood 2014). Most patients (pts) with FL eventually relapse, with progression of disease within 24 mo of first-line chemoimmunotherapy being associated with worse outcomes, emphasizing a need for more effective combinations that provide durable remissions in previously untreated (1L) FL. Differences in mechanism of action suggest that epcoritamab combined with BR may improve 1L FL outcomes. In addition, unlike CAR T-cell tx, bendamustine-containing regimens do not appear to negatively affect prognosis for pts receiving bispecific antibodies (Iacoboni et al, ASH 2023). We present initial results from arm 3 of the ongoing phase 1b/2 EPCORE NHL-2 trial (NCT04663347) evaluating fixed-duration epcoritamab + BR in 1L FL, including T-cell pharmacodynamics with this novel combination. Methods: Adults with 1L CD20+ FL grade 1-3A received subcutaneous epcoritamab + BR for 6 cycles (Cs; 28 d each) followed by epcoritamab monotherapy. Epcoritamab was administered with a 2-step (0.16 mg and 0.8 mg) step-up dosing regimen in C1 followed by 48-mg full doses (QW in C1-3, Q2W in C4-9, and Q4W thereafter for up to 2 y). The primary endpoint was ORR by PET-CT per Lugano criteria. Results: At data cutoff (May 15, 2024), 25 pts were treated with 48 mg epcoritamab + BR. The median age was 56 y (range, 32-80), median time from initial diagnosis to first dose of epcoritamab was 9 wk (range, 2-359), and median number of Cs of epcoritamab initiated was 20 (range, 3-26). Most pts had grade 2 (52%) or 3A (40%) FL; 48% and 52% had stage III and IV disease, respectively. With a median follow-up of 30.4 mo (range, 11.7-33.9+), 22 pts (88%) completed 6 Cs of epcoritamab + BR, 11 (44%) completed the full 2 y of tx, and 14 (56%) discontinued tx (progressive disease, n=1; AEs, n=9; pt withdrawal, n=3; and other reason, n=1 [investigator decision, long COVID-19]). Median relative dose intensity of BR was 99%. ORR and CR rate were both 96%. At 30 mo, an estimated 87% of responders/complete responders remained in response/CR, and estimated progression-free survival (PFS) and overall survival (OS) rates were 83% and 96%, respectively. With the majority of pts being enrolled and treated during the global COVID-19 pandemic, the most common tx-emergent AE (TEAE) was COVID-19 (72%), which led to discontinuation of epcoritamab in 7 pts (COVID-19, n=6; post-acute COVID-19 syndrome, n=1); there was 1 grade 5 COVID-19 TEAE. The next most common TEAEs were CRS (68%), nausea (64%), fatigue (52%), and injection-site reaction (52%). All CRS events were low grade (grade 1, 48%; grade 2, 20%), with most events occurring after the first full dose (C1D15). All CRS events resolved (median time to resolution, 2 d), and none led to epcoritamab discontinuation. No ICANS or clinical tumor lysis syndrome events occurred. An immunophenotypic analysis revealed a sustained reduction in peripheral CD4+ T cells, with median cell count declining from 251 cells/µL at C1D1 to 167 cells/µL at C2D15 and remaining low up to C7D1. This CD4 lymphopenia, which may be attributed to bendamustine, was primarily grade 1 or 2 based on CTCAE v5.0 criteria and could be associated with an increased risk of infection. Conversely, at C2D15, CD8+ T cells expanded 2.5-fold from baseline and generally remained elevated up to C7D1, resulting in a reduced CD4:CD8 ratio. Excluding COVID-19, the infection rates are consistent with those seen in similar regimens. Conclusions: Fixed-duration epcoritamab + BR showed deep and durable responses in 1L FL, with nearly all pts having a CR (96%) and most complete responders remaining in CR at 30 mo (87%), translating to favorable long-term outcomes (30-mo PFS, 83%; 30-mo OS, 96%). The safety profile was manageable, with no ICANS events and only low-grade, predictable CRS events, all of which resolved; however, the COVID-19 pandemic did impact study pts. These results compare favorably with BR alone and support further investigation of epcoritamab + BR in 1L FL and continued evaluation of epcoritamab as a core tx across non-Hodgkin lymphoma.