Epcoritamab with lenalidomide and tafasitamab in patients with relapsed/refractory diffuse large B cell lymphoma (ECLAT), a phase 2 investigator-initiated trial

Abstract

Abstract Background Patients with relapsed/refractory (RR) DLBCL ineligible for chimeric antigen receptor T-cell therapy and/or autologous stem cell transplant (CART/ ASCT) or with progressive disease after CART/ASCT represent a major unmet need. 3rd line and beyond (3L+) therapy for DLBCL is individualized and despite availability of several approved options, sustained remissions are obtained only in a minority of patients. Tafasitamab was FDA approved in combination with lenalidomide (tafa-len) in 2020 for 2L+ DLBCL based on the L-MIND study which showed an overall response rate (ORR) or 57.5%, complete response rate (CRR) of 40% and duration of response (DOR) of 42.9 months (mo). Epcoritamab (epco) was approved by FDA for 3L+ DLBCL in 2024 based on EPCORE-NHL1 study which showed an ORR of 61%, CRR of 38% and DOR of 15.6 months.Recent data shows that efficacy of these agents in real-world is much lower with a CRR of 12-19% for tafa-len and 23-33% for epco. Other than hematologic toxicity, these drugs do not have any overlapping toxicities and hence lend themselves to rational combinations. In fact, len can stimulate T-cell mediated killing of neoplastic cells via enhanced formation of effective immunological synapses and there is emerging data that len can enhance efficacy of chimeric antigen receptor T-cells as well as bi-specific T-cell engagers. The combination of epco and len was studied in EPCORE NHL-5 and demonstrated a higher ORR of 72% and CMR rate of 53% than single agent epco. This improvement in efficacy came at the cost of slightly increased incidence of CRS and neutropenia. Preclinical studies have also shown that the combination of tafa and a CD20xCD3 T-cell engaging antibody significantly increases tumor cell eradication both in vitro and in vivo. We hypothesize that the combination of epcoritamab with tafasitamab and lenalidomide (epco-tafa-len) will be well tolerated and effective in patients with relapsed/refractory (RR) DLBCL. Methods Study design: The ECLAT study is a phase 2, open label, single arm, single institution study of epco-tafa-len for a fixed duration of therapy of 12 cycles with each treatment cycle of 28-day duration (NCT07030699). Eligibility: Patients with R/R DLBCL are eligible if they have received at least 2 prior lines of therapy including CART or ASCT or if they have received at least one prior line of therapy and are ineligible or unable to undergo CART/ASCT due to logistical or other barriers. Prior treatment with bispecific antibodies in 1L or as bridging in 2L is permissible. Presence of CD20 and CD19 is required on most recent representative biopsy. Treatment: Patients will receive epco weekly for 12 weeks followed by once every 28 days based on the EPCORE NHL-5 study. Tafa will be given weekly for 12 weeks followed by every other week for cycles 4-12 per FDA label. Len will be given orally on days 1-21 of each cycle. We plan to start len at a lower dose of 20 mg a priori to reduce risk of hematologic toxicities in this heavily pretreated population. We also plan to allow for pragmatic dose adjustment of len based on renal function to encourage enrollment for older adults who are typically excluded due to low creatinine clearance as a function of their age when estimated by the Cockcroft Gault formula. Objectives: The primary objective is to evaluate efficacy (best CRR) of epco-tafa-len in patients with RR DLBCL. Secondary objectives include evaluation of other measures of efficacy [best ORR, progression-free survival (PFS), DOR, duration of complete response (DOCR), event-free survival (EFS), and overall survival (OS)] and to characterize the adverse event profile of the combination. Exploratory objectives include evaluation of additional measures of efficacy such as CRR and ORR at the end of therapy, 1-year PFS and OS and 2-year PFS and OS, characterization of response based on cell of origin and DLBCL subtypes by gene expression profiling (GEP), and to understand the ctDNA response kinetics of the combination. Statistics: A total of 27 patients are planned to be enrolled with a built-in safety run in of first 6 patients. The primary endpoint in best complete response rate per 2014 Lugano response criteria. Considering a null hypothesis of 35% and an alternate hypothesis (promising rate) of 60% CRR, a total of 27 patients will be needed for an alpha error of 0.05 and power of 80%. The study is open and currently recruiting patients at Memorial Sloan Kettering Cancer Center.