Epcoritamab with rituximab and lenalidomide as first-line treatment for follicular lymphoma (EPCORE NHL-2): an open-label, multicentre, phase 1/2 b trial

Background Chemotherapy-free regimens, such as rituximab and lenalidomide, are attractive first-line treatment options for follicular lymphoma, but combinations providing deeper, more durable responses are needed. We aimed to assess 3-year activity and safety of epcoritamab, a subcutaneously administered CD3 × CD20 bispecific antibody, plus rituximab–lenalidomide as first-line treatment for follicular lymphoma. Methods EPCORE NHL-2 is an open-label, phase 1b/2, clinical trial. Arm 6 of the study was conducted at 20 hospitals in six countries in Europe (Spain, the Netherlands, Czech Republic, Sweden, Belgium, and Denmark) and the USA in patients aged 18 years and older with CD20⁺, histologically confirmed grade 1–3A follicular lymphoma, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients received intravenous rituximab 375 mg/m² once per week in cycle 1 (28 days per cycle) and every 4 weeks in cycles 2–6; oral lenalidomide 20 mg daily on days 1–21 of cycles 1–12; and subcutaneous epcoritamab in a two-step-up dosing regimen of a 0·16 mg priming dose, followed by a 0·8 mg intermediate dose, then full 48 mg doses in cycle 1, 48 mg once per week in cycle 2, and 48 mg every 4 weeks in subsequent cycles for up to 2 years. The primary endpoint was investigator-assessed overall response rate by Lugano Response Criteria for Malignant Lymphoma. The full analysis set and the safety set included all patients who received one or more doses of trial drug. This study is registered with ClinicalTrials.gov ( NCT04663347 ) and is ongoing (closed to new participants). Findings Between Sept 23, 2021, and May 3, 2022, 45 patients were assessed for eligibility in Arm 6, 41 of whom were eligible and included in the full analysis and safety sets. 21 (51%) of 41 patients were male and 20 (49%) were female; 27 (66%) of patients were White, one (2%) was Asian, one (2%) was of another race, and 12 (29%) did not have race reported. At a median follow-up of 35·9 months (IQR 35·8–36·6) the overall response rate was 95% (95% CI 84–99; 39 of 41 patients). The most common grade 3–4 adverse events were neutropenia (20 [49%] of 41 patients), infections (12 [29%]), COVID-19 (six [15%]), and alanine aminotransferase increase (five [12%]). Serious adverse events occurred in 29 (71%) patients, including cytokine release syndrome (13 [32%]), serious infections (13 [32%]; one grade 2), pyrexia (three [7%]), organising pneumonia (one [2%]), pleural effusion (one [2%]), pneumonitis (one [2%]), pulmonary embolism (one [2%]), maculopapular rash (two [5%]), toxic skin eruption (one [2%]), atrial fibrillation (one [2%]), diarrhoea (one [2%]), dehydration (one [2%]), ovarian epithelial cancer (one [2%]), cerebrovascular accident (one [2%]), and thrombophlebitis (one [2%]). Treatment-related deaths occurred in three (7%) patients due to septic shock, progressive multifocal leukoencephalopathy, and COVID-19. Interpretation Epcoritamab plus rituximab–lenalidomide showed high activity in first-line treatment for follicular lymphoma, with 95% of patients having a response over 3 years of follow-up, supporting this treatment regimen as a promising approach that warrants further analysis to ascertain its role in this setting. Funding Genmab and AbbVie.