Epcoritamab monotherapy or epcoritamab with lenalidomide as first-line therapy for patients with diffuse large B-cell...

Anthracycline-free regimens are needed for older adults with newly diagnosed diffuse large B-cell lymphoma (DLBCL). We aim to evaluate the efficacy and safety of fixed-duration epcoritamab monotherapy versus epcoritamab with lenalidomide in this patient population.

This open-label, multicentre, randomised, phase 2 trial was conducted at 44 hospitals across 11 countries in Europe and Asia. Patients had newly diagnosed, histologically confirmed CD20-positive large B-cell lymphoma, were ineligible for anthracycline-based chemoimmunotherapy (age ≥80 or ≥75 years with clinically significant comorbidities), had Ann Arbor stage II-IV disease, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. In stage 1, patients were randomly assigned (1:1) to epcoritamab monotherapy or epcoritamab with lenalidomide using a validated interactive response technology system and stratified by the International Prognostic Index (<3 vs ≥3) and ECOG performance status (0-1 vs 2). Epcoritamab was administered subcutaneously using a two step-up dosing schedule (0·16 mg on cycle 1 day 1 and 0·8 mg on cycle 1 day 8), followed by full 48 mg doses once per week in 28-day cycles during cycles 1-3 and once every 4 weeks during cycles 4-12 for up to 12 cycles. Lenalidomide (10 or 20 mg) was given orally once a day on days 1-21 of 28-day cycles for up to 12 cycles. Based on stage 1, one of the treatment regimens was selected for expansion in stage 2. The primary endpoint was investigator-assessed complete response rate (as of the data cutoff on Dec 5, 2025; Lugano criteria) in the full analysis set (all randomly assigned patients in stage 1 and in all treated patients in stage 2). Safety was analysed in patients who received ≥1 dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT05660967 (active, not recruiting).

Between March 8, 2023, and May 14, 2025, 111 patients were assessed for eligibility (88 in stage 1 and 23 in stage 2) and 108 were treated. Median age was 83·0 years (IQR 80·0-86·0). 51 (47%) of 108 were male, 57 (53%) were female, and 87 (81%) were White. In stage 1, 44 patients each were randomly assigned to epcoritamab monotherapy or epcoritamab with lenalidomide and two did not receive treatment. At data cutoff, the complete response rate in stage 1 was 63·6% (95% CI 47·8-77·6; in 28 of 44 patients) in the epcoritamab monotherapy group and 45·5% (30·4-61·2; in 20 of 44) in the epcoritamab with lenalidomide group. The most common treatment-emergent adverse events (grade ≥3) were infections (eight [18%] of 44 patients) and fatigue (six [14%]) with epcoritamab monotherapy versus neutropenia (17 [40%] of 42) and infections (16 [38%]) with epcoritamab with lenalidomide; with serious adverse events in 28 (64%) versus 34 (81%). Treatment-emergent deaths occurred in six (14%) patients in the monotherapy group (cytomegalovirus infection reactivation, COVID-19 pneumonia, SARS-COV-2 infection, tumour lysis syndrome, neuroendocrine tumour of the lung, tumour haemorrhage) and six (14%) in the combined group (pneumonia, COVID-19 pneumonia, sepsis, general physical health deterioration, multiple organ dysfunction syndrome, acute cardiac failure). Based on differences in complete response rates and safety, epcoritamab monotherapy was selected for stage 2 and one patient did not receive treatment. In the epcoritamab monotherapy group, the complete response rate was 45·5% (24·4-67·8; in ten of 22) in stage 2 and 57·6% (44·8-69·7; in 38 of 66) across stages 1 and 2. The most common treatment-emergent adverse events (grade ≥3) among all patients who received epcoritamab monotherapy were infections (16 [24%]), neutropenia (eight [12%]), and hypertension (seven [11%]); with serious adverse events in 46 (70%). Treatment-emergent deaths occurred in two (3%) patients in stage 2 (multiple organ dysfunction syndrome and acute respiratory failure).

Fixed-duration epcoritamab monotherapy showed promising complete response rates and a manageable safety profile in older adults with newly diagnosed DLBCL and comorbidities, with slight differences between stages 1 and 2. Continued investigation of epcoritamab as a first-line chemotherapy-free treatment option is warranted.

Genmab and AbbVie.