A novel bispecific antibody has demonstrated clinically meaningful activity in patients with Richter transformation, one of the most aggressive and difficult-to-treat forms of B-cell lymphoma, according to results from an international early-phase clinical trial.
Richter transformation occurs when chronic lymphocytic leukaemia or small lymphocytic lymphoma evolves into diffuse large B-cell lymphoma. Outcomes remain poor, with median survival typically limited to 6–12 months, particularly in patients with high-risk disease features or prior therapy.
International Trial Design And Patients
The multicentre, open-label phase 1b/2 study evaluated epcoritamab, a subcutaneous CD3×CD20 bispecific antibody, in patients with histologically confirmed Richter transformation. The trial was conducted at 24 centres across nine countries (Australia, Belgium, Denmark, Germany, Israel, Italy, Spain, The Netherlands, and USA).
The current analysis focused on 42 patients treated with epcoritamab monotherapy in the dose-expansion phase. Participants were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and had received up to two previous lines of Richter transformation-directed therapy. The median age was 69 years, and 76% of patients were male. Half of the cohort received epcoritamab as first-line treatment for Richter transformation.
Epcoritamab was administered using a step-up dosing schedule, followed by weekly, biweekly, and then monthly dosing until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate, evaluated against a prespecified alternative hypothesis of 50%.
Response Rates Across Risk Groups
At a median follow-up of 22.9 months, 20 of 42 patients achieved an objective response, corresponding to an overall response rate of 47.6%. While this did not meet the prespecified efficacy threshold (50%), responses were more frequent in certain subgroups.
Among patients treated in the first-line setting, the overall response rate was 57.1%, compared with 38.1% in those treated in the second line or later. In patients with TP53 aberrations and or del(17p), features associated with particularly poor prognosis, the response rate was 40%.
Safety Profile And Future Directions
The safety profile of epcoritamab was consistent with previous studies. Common grade 3–4 adverse events included neutropenia in 45% of patients, anaemia and thrombocytopenia each in 38%, and infections in 21%, pneumonia in 10% and COVID-19 in 5% of patients. Cytokine release syndrome occurred in 86% of patients, though most cases were low grade, with grade 3 events reported in 7%. Neurotoxicity was limited to grade 1–2 events.
Investigators concluded that epcoritamab monotherapy demonstrated meaningful antitumour activity in this high-risk population. Although the primary efficacy threshold was not met, the results support continued investigation of epcoritamab, including in combination regimens, as a potential new option for patients with Richter transformation.
Reference
Kater PAP et al. Epcoritamab monotherapy for Richter transformation (EPCORE CLL-1): findings from a single-arm, multicentre, open-label, phase 1b/2 trial. The Lancet Hematology. 2025;13(1):e8-21.
