Efficacy and Safety of Epcoritamab Monotherapy in Patients with Relapsed or Refractory LBCL Not Previously Exposed to CAR T: Subanalysis of the Epcore NHL-1 Trial

Introduction: Although chimeric antigen receptor T-cell therapies (CAR T) are approved in the relapsed or refractory (R/R) large B-cell lymphoma (LBCL) setting, their usage may be limited by patient (pt) eligibility/fitness, accessibility, and/or manufacturing timelines and consistency. Epcoritamab, a subcutaneous (SC) CD3xCD20 T-cell-engaging bispecific antibody available off the shelf, has led to deep, durable responses with manageable toxicity in pts with R/R LBCL in the pivotal phase 2 EPCORE® NHL-1 trial (NCT03625037), and is approved for the treatment of adults with different types of R/R LBCL and follicular lymphoma (FL) after ≥2 prior lines of therapy. Epcoritamab has also been shown to be effective in pts post CAR T (overall response rate [ORR]/complete response [CR] rate: 54%/34%; Phillips et al, ASH 2022). Here, we report efficacy and safety results from a subanalysis of pts not previously treated with CAR T (CAR T naive) in the EPCORE NHL-1 trial. Methods: Adult pts with R/R CD20+ LBCL (including diffuse LBCL [DLBCL], high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and FL grade 3B) and ≥2 prior lines of systemic antilymphoma therapy were treated with epcoritamab SC (2 step-up doses followed by 48-mg full doses) in 28-d cycles. Pts were treated QW, cycles 1-3; Q2W, cycles 4-9; and Q4W, cycles ≥10, until progressive disease or unacceptable toxicity. Corticosteroid prophylaxis was used during cycle 1. The primary endpoint was ORR per Lugano criteria. Minimal residual disease (MRD) was evaluated using the clonoSEQ® (Adaptive Biotechnologies) ctDNA assay. Results: A total of 96 CAR T-naive pts with R/R LBCL were treated with epcoritamab. Median age was 69 y (range, 31-83 [median age in the total R/R LBCL population (N=157), 64 y]) and 60% were male. The median number of prior lines of therapy was 3 (range, 2-11), and 50 pts (52%) had ≥3 prior lines. At data cutoff (May 3, 2024), 13 pts (14%) remained on epcoritamab; the most common reasons for treatment discontinuation were progressive disease in 52 pts (54%) and adverse events in 22 pts (23%). The ORR and CR rate per investigators were 61% and 45% (median study follow-up, 37.3 mo [range, 0.3+ to 45.5]). Median duration of response was 18.4 mo (95% CI, 9.7-30.4). Median duration of CR was 28.6 mo (95% CI, 15.8 to not reached [NR]) and an estimated 46% remained in CR at 36 mo. Median progression-free survival (PFS) was 4.3 mo (95% CI, 3.4-10.9) overall and 33.3 mo (95% CI, 19.4-NR) among complete responders. Median overall survival (OS) was 15.4 mo (95% CI, 11.0-27.8) overall and NR (95% CI, 27.8-NR) among complete responders. At 36 mo, an estimated 40% of pts overall and 83% of complete responders had not initiated their next antilymphoma therapy. Among 35 pts who received subsequent antilymphoma therapy, 10/35 (29%) received CAR T; 6 of these 10 pts remain alive at data cutoff. Of 74 MRD-evaluable pts, 33 (45%) were MRD negative. In a cycle 3 day 1 landmark analysis, estimated 36-mo rates of PFS/OS were 42%/52% among MRD-negative pts and 16%/31% among MRD-positive pts. The most common treatment-emergent AEs (TEAEs) were cytokine release syndrome (CRS; 60%), diarrhea (24%), pyrexia (23%), fatigue (22%), neutropenia (22%), and injection-site reaction (21%). Fatal TEAEs were reported in 18 pts; 9 of 18 events were related to COVID-19. TEAEs led to treatment discontinuation in 22 pts (23%) and were most commonly COVID-19 pneumonia (8%), COVID-19 (3%), and pneumonia (2%). CRS events were mostly grade 1 (33%) or grade 2 (23%); 4% of pts had grade 3 CRS. CRS was most common following the first full (cycle 1 day 15) dose (median time to onset, 20 h). CRS resolved in all but 2 pts and led to treatment discontinuation in 1 pt. ICANS occurred in 7 pts (7%; grade 1, 6%; grade 5, 1%). Clinical tumor lysis syndrome occurred in 2 pts (2%; each grade 3). Immunoglobulin G levels decreased by a median of ~20% after the start of epcoritamab treatment (baseline median: 653.0 mg/dL) and remained stable over time. Conclusions: With over 3 years of follow-up, single-agent epcoritamab demonstrated deep and durable responses and manageable side effects in CAR T-naive pts with R/R LBCL, as demonstrated by this subgroup analysis. Results were consistent with those seen in the overall EPCORE NHL-1 LBCL population, considering differences in baseline characteristics, and show that epcoritamab can be administered safely and effectively before or after CAR T for the treatment of R/R LBCL.