Evaluation of ctDNA in a phase I/II trial in relapsed or refractory large B‐cell lymphoma of epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T‐cell–engaging antibody

Introduction: The emergence of novel, more potent therapeutics in the treatment of patients with large B-cell lymphoma (LBCL) has resulted in higher rates of responses and highlighted a need for additional methods, such as minimal residual disease (MRD), to determine the depth and quality of response and potentially guide duration of treatment. Epcoritamab (DuoBody®-CD3xCD20) is a subcutaneously (SC) administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, inducing activation and cytotoxic activity of T cells for the killing of malignant CD20 B cells. In the pivotal epcoritamab trial, a correlation was demonstrated between MRD by clonoSEQ® (Adaptive Biotechnologies) and long-term outcomes. These findings led to additional analyses to further clarify the clinical use of ctDNA. As the evaluation of ctDNA in LBCL has not been standardized, we have expanded our investigation of the utility of ctDNA measurements from the initial analysis with the clonoSEQ assay to the AVENIO ctDNA assay (Roche). Here we present additional exploratory analyses of ctDNA using the AVENIO assay. Methods: Patients with relapsed/refractory (R/R) LBCL enrolled in EPCORE NHL-1 expansion phase (NCT03625037) received SC epcoritamab administered in 28-d cycles. ctDNA was measured using the clonoSEQ and AVENIO ctDNA assays at protocol-specified timepoints. Specimens were collected in EDTA and Streck cfDNA tubes, respectively, based on the recommended sample type at the time of study initiation. Plasma ctDNA levels were quantified per sample as count per mL (CPM) and mutant molecules per mL (MMPM) for clonoSEQ and AVENIO, respectively. Results: ctDNA quantification was concordant between the assays when within the dynamic range of the clonoSEQ assay (>80% in paired samples tested); however, a greater sensitivity of the AVENIO assay was observed, allowing further exploratory analyses of ctDNA using this platform. Consistent with prior observations, baseline ctDNA levels were associated with key clinical parameters, including LDH, TMTV, ECOG, and IPI. In patients who responded to epcoritamab, ctDNA levels decreased rapidly, with the majority of patients achieving CR having a deep ctDNA response by C3D1. Additional patients achieved MRD-negative status at later evaluations with continued therapy. MRD-negative status at C3D1, measured as absolute or relative change from baseline, was associated with longer progression free survival (PFS) and sustained MRD negativity throughout the duration of treatment. The research was funded by: Genmab A/S and AbbVie Keywords: Aggressive B-cell non-Hodgkin lymphoma, Liquid biopsy, Minimal residual disease Conflicts of interests pertinent to the abstract. D. Soong Employment or leadership position: Genmab C. Thieblemont Consultant or advisory role: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche, Incyte, Janssen, Takeda Honoraria: AbbVie, Amgen, Bayer, Cellectis, Gilead Sciences, Incyte, Janssen, Kite, Novartis, Takeda Research funding: BMS/Celgene, Hospira, Roche Educational grants: AbbVie, Amgen, BMS/Celgene, Cellectis, Gilead Sciences, Kite, Novartis, Roche J. Karavitis Employment or leadership position: Genmab B. Hess Consultant or advisory role: ADC Therapeutics, BMS P. Caimi Consultant or advisory role: ADC Therapeutics, BMS, Beigene, Genentech, Lilly, Takeda, Kite pharma, Incyte, Novartis, MEI pharma Research funding: Genentech, Abbvie, ADC Therapeutics T. Feldman Consultant or advisory role: AbbVie, AstraZeneca, Epizyme, Genmab, Gilead/Kite, Karyopharm, Takeda, Seagen Other remuneration: Seagen: Speakers Bureau M. Hutchings Consultant or advisory role: AbbVie, Celgene, Genmab, Janssen, Roche, Takeda Research funding: Celgene, Genentech, Genmab, Incyte, Janssen, Novartis, Roche, Takeda (All Paid to Institution) A. Sureda Employment or leadership position: AbbVie Consultant or advisory role: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, Mundipharma, Bluebird Honoraria: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite Research funding: Takeda Educational grants: Takeda, BMS/Celgene, Roche Other remuneration: Takeda, BMS/Celgene, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Speakers Bureau E. Szafer-Glusman Employment or leadership position: AbbVie M. Sacchi Employment or leadership position: Genmab M. Jure-Kunkel Employment or leadership position: Genmab N. Adya Employment or leadership position: Genmab C. Chiu Employment or leadership position: Genmab