Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, with approximately 25,000 new cases diagnosed annually in the US. Anthracycline-based chemotherapy such as R-CHOP or pola-R-CHP is the current standard first-line therapy for DLBCL. Anthracyclines have been a key drug in the treatment of DLBCL; however, they are associated with risk of cardiotoxicity including heart failure. Older patients are likely to be particularly susceptible due to comorbidities such as hypertension and diabetes, as well as limited cardiac reserve. The median age of onset of DLBCL is around 65 years, and about one-third of patients are diagnosed at age >75 years. For those older, unfit/frail patients, reduced dose chemoimmunotherapy with R-miniCHOP has been the current standard. However survival outcomes from R-miniCHOP are suboptimal with 2-year progression-free survival (PFS) of approximately 40-45%. CD20 x CD3 bispecific antibody monotherapy can achieve approximately 60% response rate in a recent small phase I/II trial for older/unfit patients with newly diagnosed DLBCL. However, the complete response (CR) rate, long-term remission, and potential for cure may be suboptimal and may possibly underperform R-miniCHOP, which itself remains toxic. Therefore, there is an unmet need for an effective and tolerable non-anthracycline treatment for patients who cannot receive anthracycline-based therapy.

We hypothesize that epcoritamab with non-anthracycline chemotherapy, R-miniCVP, can achieve high CR rates comparable to current standard treatment R-miniCHOP.

Study Design and Methods: This is an open-label, single-arm phase 2 trial at MD Anderson Cancer Center. The primary objective of this trial is to determine the CR rate following epcoritamab in combination with R-miniCVP for older, unfit/frail patients or patients with heart failure with newly diagnosed DLBCL. Patients who are histologically diagnosed with DLBCL and ineligible for anthracycline-based cytotoxic chemoimmunotherapy are eligible for the trial: age ≥80 or unfit/frail per FIL simplified geriatric assessment, ejection fraction (EF) <50% but ≥ 30% or previous cardiotoxic cancer treatment who cannot receive more anthracycline or previous cardiotoxic cancer treatment with anthracycline. Patients will receive standard R-miniCVP for 1 cycle for debulking, and epcoritamab is added to R-miniCVP from second cycle: 0.16mg subq on C2D1, 0.8mg subq on C2D8 and 48mg subq on C2D15. Following third cycle, 48mg subq epcoritamab will be added on day 1 of each 21-day cycle. Patients who achieve CR after 6 cycles will complete treatment. Patients with a best response of stable disease after 6 cycles will come off the treatment. Patients with a best response of partial response after 6 cycles will continue 48mg subq epcoritamab every 4 weeks from cycles 7-12. The primary endpoint of the study is the CR rate after 6 cycles defined by Lugano criteria. Secondary endpoints include duration of response, PFS, and overall survival. Correlative studies are planned to investigate the contribution of pre-treatment tumor and T-cell lymphocyte characteristics including activation/exhaustion and tumor infiltration that are associated with outcomes following epcoritamab and R-miniCVP, measurement of circulating tumor DNA (ctDNA) as a kinetic biomarker for response to treatment, and to understand mechanisms of response and resistance to epcoritamab and R-miniCVP.

Conclusion: The trial opened in 1/2024 and is actively recruiting patients (NCT06045247).

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2025
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