Abstract Introduction: BR is a widely used 1L regimen in FL; however, there remains a need for novel combination therapies that achieve deeper and more durable remissions with manageable safety. Epcoritamab, a CD3×CD20 bispecific antibody, has been approved as monotherapy for relapsed/refractory FL after ≥2 prior lines of therapy based on the results of the EPCORE® NHL-1 trial. In the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), treatment with fixed-duration epcoritamab + BR demonstrated high antitumor activity in 1L FL. Here, we report long-term efficacy and safety results with median follow-up of more than 3 years. Methods:Adults with 1L CD20+ FL grade 1–3A received fixed-duration epcoritamab + BR for six 28-day cycles (C1–6) followed by epcoritamab monotherapy (total treatment duration: ≤2 years). Epcoritamab was administered subcutaneously QW as a 2 step-up dose regimen (0.16 mg, 0.8 mg) in C1, then 48-mg full doses QW in C1–3, Q2W in C4–9, and Q4W from C10+. Bendamustine 90 mg/m² was given on days 1–2 of C1–6 and rituximab 375 mg/m² Q4W in C1–6. Primary endpoint was overall response rate (ORR) by Lugano criteria. Results: At data cutoff (DCO; April 9, 2025), 25 patients received epcoritamab + BR. Median age was 56 years; 56% were male. All patients met GELF criteria, 48% had bone marrow involvement, 28% had bulky disease (≥7 cm), 100% had Ann Arbor stage III/IV, and 56% had a FLIPI score of 3–5. Eleven patients (44%) completed treatment per protocol and 14 (56%) discontinued; 9 discontinuations were due to AEs (7 COVID-19 related) after ≥8 treatment Cs. Median relative dose intensity was 99% for BR in C1–6. In the monotherapy phase, a median of 14 Cs of epcoritamab were administered. With a median follow-up of 41.3 months, best ORR and complete response (CR) rate were both 96%. Median time to response and to CR were both 1.5 months (range, 1.1–2.6 and 1.1–5.6, respectively). Median duration of response, duration of CR (DOCR), PFS, and OS were not reached. The 3-year estimates for DOR, DOCR, PFS, and OS were 87%, 87%, 83%, and 96%, respectively. PFS was consistently high overall and in both low- and high-risk subgroups. Among the 24 patients with CR, 11 discontinued treatment for reasons other than progressive disease or death, had a response measurement post discontinuation, and had CR at end of treatment (median treatment duration: 12.7 months); with a median follow-up for DOCR of 23.5 months post-treatment, CR was maintained in 9 of these 11 patients (82%) at DCO. All 11 patients who completed 2 years of treatment per protocol had CR at the end of treatment and 9 (82%) maintained CR as of DCO with a median follow-up of 17.5 months post-treatment. With ~11 months of additional follow-up since the last DCO, no new safety signals were reported (Brody JD, et al. Blood 2024;144Suppl1: 1627). Grade ≥3 TEAEs and serious TEAEs, including neutropenia and infection, primarily occurred in the first 24 weeks of treatment, coinciding with the epcoritamab + BR treatment period, and rates improved over time during the epcoritamab monotherapy treatment period. Since the prior DCO, 3 patients experienced new COVID-19 infection events (grade 1–2). There was a sustained reduction in peripheral CD4+ T cells, whereas peripheral CD8+ T cells expanded after the first full dose, resulting in a reduced CD4:CD8 ratio. Conclusions: Fixed-duration epcoritamab + BR demonstrated deep and durable responses at a median follow-up of 41.3 months, with a 96% CR rate and estimated 3-year DOCR of 87% and PFS of 83%, underscoring the long-term efficacy of this 1L treatment combination in FL. The safety profile remained consistent beyond the 2-year fixed treatment period with no new safety signals or late-onset toxicities, supporting the long-term feasibility of this combination. These data reinforce the efficacy of epcoritamab + BR as a 1L treatment option with a manageable safety profile aligned with those of the individual agents, supporting the combinability of epcoritamab as a core therapy in this setting.
Offner et al. (Mon,) studied this question.