Fixed-Duration Epcoritamab + R-Mini-CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: Updated Results from Arm 8 of the Epcore NHL-2 Trial

Introduction: A standard treatment for patients (pts) with previously untreated (1L) diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, certain pts are ineligible to receive full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. Dose-attenuated R-CHOP (R-mini-CHOP) has become a standard first-line regimen for these pts despite suboptimal outcomes, including overall response rates (ORRs) and complete response (CR) rates of approximately 70% and 40%-60%, respectively, and a 2-y progression-free survival (PFS) rate of only 47%. Epcoritamab, a CD3xCD20 bispecific antibody, in combination with R-mini-CHOP demonstrated encouraging efficacy (ORR, 100%) and a manageable safety profile in pts with 1L DLBCL who were ineligible for full-dose R-CHOP (Vermaat et al, ASH 2023; median follow-up, 9.4 mo). Here, we report updated results with longer follow-up from arm 8 of the EPCORE® NHL-2 trial (phase 1b/2; NCT04663347) evaluating epcoritamab + R-mini-CHOP in this population. Methods: Adult pts with 1L CD20+ DLBCL who were ineligible for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [>6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Pts received fixed-duration subcutaneous epcoritamab (QW, cycles [Cs] 1-2 [21 d each]; Q3W, C3-6 [21 d each]; Q4W, C7-8 [28 d each]; with step-up dosing in C1 [0.16 mg on C1D1 and 0.8 mg on C1D8]) + R-mini-CHOP (Q3W, C1-6). The primary endpoint for this population was ORR as determined by PET-CT and Lugano criteria. Minimal residual disease (MRD) negativity was assessed as a secondary endpoint using the exploratory AVENIO ctDNA method. Results: As of May 15, 2024, 28 pts were treated with epcoritamab 48 mg + R-mini-CHOP. The median age was 81 y (range, 74-90), 19 pts (68%) had IPI 3-5, 15 pts (54%) had stage IV disease, and 11 pts (39%) had bulky disease (≥7 cm); 13 pts (46%) had germinal center B-cell (GCB)-type disease, 11 pts (39%) had non-GCB type, and 4 pts (14%) had unknown type. The median follow-up was 16.8 mo (range, 2.5+ to 23.1), with 22 pts (79%) having completed treatment per protocol and none remaining on treatment. Median relative dose intensity of R-mini-CHOP was ≥94%. ORR was 89% (25/28), with CR in 82% of pts (23/28). An estimated 92% of responders remained in response at 12 mo, and an estimated 91% of complete responders remained in CR at 12 mo. The estimated 12-mo PFS and overall survival rates were 88% and 96%, respectively. Of 21 MRD-evaluable pts, 20 (95%) were MRD negative using the AVENIO ctDNA method and a cutoff of <1 mutant molecule per mL. The most common treatment-emergent AEs (TEAEs) of any grade (occurring in ≥25% of pts) were CRS (54%), neutropenia (43%), constipation (29%), fatigue (29%), anemia (25%), fall (25%), and pneumonia (25%). All CRS events were low grade (25% grade 1, 29% grade 2), and most events were observed after the first full dose of epcoritamab. All CRS events resolved, and 1 pt (4%) discontinued epcoritamab due to CRS. No ICANS or clinical tumor lysis syndrome events were reported. Overall, 3 pts (11%) discontinued epcoritamab due to TEAEs, including 1 pt (4%) who had grade 5 TEAEs (confusional state not related to treatment and cytomegalovirus infection reactivation considered related to treatment in a pt aged 90 y also diagnosed with acute cerebrovascular accident). Conclusions: Epcoritamab + R-mini-CHOP treatment continues to demonstrate encouraging and durable efficacy in pts with 1L DLBCL who were not candidates for full-dose R-CHOP, including elderly and high-risk pts. These results are promising compared with historical outcomes with R-mini-CHOP. The safety profile was manageable, with no new safety signals, no ICANS, and only low-grade CRS events. These results support further clinical evaluation of fixed-duration epcoritamab in combination with chemotherapy in early lines of therapy, including in pts with high-risk features.