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.

7002 Background: The median age at diagnosis of diffuse large B-cell lymphoma (DLBCL) is approximately 65 years, with nearly one third of patients in the US diagnosed at age >75 years. This older unfit/frail population is particularly vulnerable to treatment-related toxicity due to comorbidities and limited cardiac reserve, frequently leading to treatment discontinuation, and outcomes with standard attenuated anthracycline-based chemoimmunotherapy remain suboptimal. There is therefore a critical unmet need for effective, better-tolerated non-anthracycline treatments. We hypothesize that epcoritamab combined with non-anthracycline chemotherapy (R-miniCVP) can achieve high and durable CR rates. Methods: This is an open-label, single-arm phase 2 trial conducted at MD Anderson Cancer Center (NCT06045247). Eligible patients have histologically confirmed DLBCL and are unfit/frail per FIL simplified geriatric assessment, or not eligible for anthracycline due to reduced ejection function (<50%), or prior anthracycline exposure therapy. Patients receive one cycle of R-miniCVP for debulking, followed by epcoritamab added from cycle 2 using step-up dosing, then 48 mg on day 1 of each subsequent cycle. After 6 cycles, patients achieving CR complete treatment, while patients with PR continue epcoritamab to 12 cycles. The primary endpoint is CR rate after 6 cycles. Results: We plan to enroll 40 patients. At the data cutoff, 22 patients have completed six cycles of therapy. The median age of 22 patients was 80 years (range, 71-87); 27% had PS 2, and 86% had an IPI ≥3. All patients completed planned treatment. The CR rate after 6 cycles was 86% (95% CI, 65-97%). Two patients achieved PR and continue on epcoritamab. One patient achieved PR after cycle 3 but progressed after cycle 6 and subsequently died of progressive lymphoma following 2 additional lines of therapy. With a median follow-up of 11 months (range: 5-23 months), the 1-year progression-free survival was 94.7% (95% CI, 68-99%). Cytokine release syndrome occurred in 12 patients (55%), all grade 1 and occurred around C2D15, which fully resolved in 1-2 days in all patients. Four of them received tocilizumab. One patient developed grade 2 neurotoxicity after C2D15, which resolved within 24 hours after switching prednisone to dexamethasone. The trial protocol was amended to change prophylactic steroid from prednisone to dexamethasone, after which no further neurotoxicity was observed. Conclusions: The combination of epcoritamab with R-mini-CVP demonstrated encouraging efficacy with a favorable tolerability profile in older, unfit or frail patients who may be unable to tolerate full-dose chemotherapy. Based on these promising early-phase results, the study is planned for expansion into a multicenter trial with a larger patient cohort. Clinical trial information: NCT06045247 .