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 (March 24, 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 DLBCL (HR 0.42, 95% CI: 0.24-0.75) cohorts. Combining undetectable ctDNA with achievement of PET-CT 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 towards shorter PFS, whereas the EZB subtype trended towards longer PFS, versus the rest of the cohort. MRD by ctDNA may be prognostic of outcomes with odronextamab in FL/DLBCL and could form the basis of response-guided treatment paradigms. This trial is registered at www.ClinicalTrials.gov as NCT03888105.