Diffuse large B-cell lymphoma (DLBCL) is most commonly diagnosed in older adults, with a median age of approximately 65 years and nearly one-third of patients diagnosed after age 75. In this population, comorbidities and reduced cardiac reserve frequently limit the use of standard anthracycline-containing regimens. As such, there is a clear need for more effective and better-tolerated therapeutic options.

Investigators at MD Anderson Cancer Center are evaluating the combination of epcoritamab, a CD3×CD20 bispecific antibody, with rituximab plus reduced‑dose cyclophosphamide, vincristine, and prednisone (R-miniCVP), a non-anthracycline chemotherapy backbone, in this high-risk group. This open-label, single-arm phase 2 study (NCT06045247) enrolls patients with newly diagnosed DLBCL who are deemed unfit or frail based on geriatric assessment criteria, or who are ineligible for anthracyclines due to cardiac dysfunction or prior exposure.

The treatment regimen includes 1 initial cycle of R-miniCVP for disease debulking, followed by the addition of epcoritamab starting in cycle 2 using a step-up dosing strategy, then continued at a fixed dose in subsequent cycles. After 6 cycles, patients with a complete response (CR) stop treatment, whereas those with a partial response (PR) may continue epcoritamab for up to 12 cycles. The primary endpoint is the CR rate after 6 cycles.

At the time of this interim analysis (May 5, 2026), 26 patients had completed the first 6 cycles of therapy. The median age was 80 years, the majority of patients (88%) had International Prognostic Index ≥3, and 27% of patients had an ECOG Performance Status of 2. Despite the high-risk nature of this cohort, the regimen demonstrated impressive efficacy. The CR rate after 6 cycles was 88%. One patient initially responded but later experienced disease progression after cycle 6 and ultimately died following subsequent lines of therapy. With a median follow-up of 11.6 months, the estimated 1-year progression-free survival rate was notably high at 88.5% (95% CI, 59.3-97.2), and the 2-year overall survival rate was 92.3% (95% CI, 56.6-98.9) suggesting strong early disease control.

Importantly, treatment was well tolerated across this frail population. All patients were able to complete the planned 6 cycles, highlighting the feasibility of the regimen. Cytokine release syndrome, a known risk with bispecific antibodies, occurred in 46% of patients with 42% being grade 1 and 4% being grade 2. Only a small subset of these patients (15%) required tocilizumab for management. Only 1 case of grade 2 neurotoxicity was reported, which resolved rapidly with corticosteroid adjustment. Following a protocol amendment replacing prednisone with dexamethasone for prophylaxis, no additional neurotoxicity events were observed.

These early findings suggest that epcoritamab combined with R-miniCVP may offer a highly effective and well-tolerated non-anthracycline option for older or frail patients with DLBCL. The high response rates and favorable safety profile are particularly notable given the limited treatment options and historically poor outcomes in this group. Based on these promising interim results, plans are underway to expand the study into a larger, multicenter trial to further validate this approach and define its role in frontline therapy for this underserved population.

Source: Chihara D, et al. Phase 2 trial of epcoritamab in combination with rituximab-mini CVP for older unfit/frail or anthracycline-ineligible adult patients with newly diagnosed diffuse large B-cell lymphoma: interim futility analysis. Presented at: ASCO Annual Meeting. May 29-June 2, 2026; Chicago, IL. Abstract 7002.