Background: Improving the safety of epcoritamab by reducing the incidence and severity of CRS and ICANS may enhance its accessibility and reduce healthcare resource utilization. In the pivotal EPCORE NHL-1 study (phase 1/2; NCT03625037), epcoritamab treatment (tx) led to high overall (ORR) and complete response (CR) rates of 82% and 63%, respectively, in a cohort of patients (pts) with R/R FL. Safety was manageable, with CRS events being primarily low grade. Here we report the first results from the fully enrolled EPCORE NHL-1 FL C1 OPT cohort investigating mitigation strategies for CRS with no mandatory hospitalization in pts with R/R FL receiving epcoritamab. Methods: Pts with CD20⁺ R/R FL (grade [G] 1–3A) with ≥2 prior tx lines received subcutaneous (SC) epcoritamab in 3 step-up doses (0.16, 0.8, and 3 mg) in C1, followed by 48-mg full doses in 28-d Cs (QW, C1–3; Q2W, C4–9; Q4W, C≥10) until disease progression or unacceptable toxicity. Pts received dexamethasone prophylaxis and hydration recommendations in C1. Hospitalization for CRS monitoring was not mandated. The primary endpoints were rates of any-grade and G≥2 CRS. Secondary endpoints included response per Lugano criteria, minimal residual disease (MRD) in peripheral blood, and safety. Results: As of Jan 8, 2024, 86 pts with R/R FL were enrolled in this C1 OPT cohort (median follow-up, 5.7 mo). Pt characteristics were similar in the C1 OPT and pivotal cohorts. An overview of CRS, ICANS, and clinical tumor lysis syndrome (CTLS) events in these cohorts is in Table. CRS events primarily occurred during C1, and none led to epcoritamab discontinuation. Consistent with the lower rates of CRS with C1 OPT, IL-6 levels 24 h after the first full dose were lower than those observed in the pivotal cohort. Of 82 pts who received the first full dose in the C1 OPT cohort, 44 (54%) received outpatient CRS monitoring based on investigator discretion. Among 81 response-evaluable pts in the C1 OPT cohort, ORR was 91% and CR rate was 68%. Median times to response and CR were 1.4 mo and 1.5 mo, respectively. Among MRD-evaluable pts (n=44), MRD negativity was achieved in 64% (n=28). Conclusions: CRS mitigation measures in C1 further improved the safety of epcoritamab in pts with R/R FL by substantially reducing the rate and severity of CRS compared with previous reports. For pts treated in the outpatient setting, CRS was identified and appropriately treated, with few G2 events, no G≥3 events, and all events resolving. Response rates, MRD-negativity rate, and time to CR suggest that C1 OPT did not impact efficacy. These data support the potential use of SC epcoritamab as an off-the-shelf, outpatient tx option for pts with R/R FL. Clinical trial information: NCT03625037.

^aData cutoff: Apr 21, 2023.

^bNo G≥4 CRS.

^cNo G≥3 ICANS.