Early clearance of circulating tumor DNA and association with odronextamab response in relapsed/refractory FL and DLBCL

Odronextamab, a CD20×CD3 bispecific antibody, demonstrated robust efficacy and durable responses, with a generally manageable safety profile, in patients with relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the phase 2 ELM-2 study. This exploratory analysis evaluated the prognostic value of minimal residual disease (MRD) status and tumor molecular profiles, based on circulating tumor DNA (ctDNA) analysis, for determining patient outcomes in ELM-2. Baseline and on-treatment ctDNA samples were used for MRD evaluation (AVENIO Oncology Assay Non-Hodgkin Lymphoma test); baseline ctDNA samples were also used for molecular profiling. At data cutoff (24 March 2025), the cycle 4, day 15 (C4D15) biomarker population with available ctDNA results comprised 60 patients with FL and 77 patients with DLBCL. Undetectable ctDNA at C4D15 was associated with prolonged progression-free survival (PFS) in the FL (hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.14-0.67) and the DLBCL cohorts (HR, 0.42; 95% CI, 0.24-0.75). Combining undetectable ctDNA with achievement of positron emission tomography-computed tomography complete response at C4D15 was associated with extended PFS in both cohorts. Among patients with progressive disease per Lugano criteria, most had detectable ctDNA at C4D15 (FL, 15/19; DLBCL, 28/35). In the DLBCL cohort, LymphGen analysis by ctDNA showed that the MCD subtype trended toward shorter PFS, whereas the EZB subtype trended toward longer PFS, compared with the rest of the cohort. MRD by ctDNA may be prognostic of outcomes with odronextamab in FL and DLBCL and could form the basis of response-guided treatment paradigms. This trial is registered at www.ClinicalTrials.gov as #NCT03888105.