TOTAL METABOLIC TUMOR VOLUME AND CIRCULATING TUMOR DNA AS EARLY PROGNOSTIC FACTORS IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: RESULTS FROM THE PHASE 3 STARGLO TRIAL.

Abstract

Background The Phase 3 STARGLO trial (NCT04408638) demonstrated significant 3-year overall survival and progression-free survival (PFS) benefits with fixed-duration glofitamab in combination with gemcitabine and oxaliplatin (GemOx; Glofit-GemOx), supporting its curative potential in autologous stem cell transplant (ASCT)-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Nevertheless, identifying robust baseline and on-treatment biomarkers for the prediction of long-term outcomes remains a critical need. Aims To evaluate the prognostic value of baseline total metabolic tumor volume (TMTV) alongside baseline and longitudinal circulating tumor DNA (ctDNA) for the prediction of long-term outcomes in the STARGLO trial. Methods Patients (pts) with ASCT-ineligible R/R DLBCL were randomized 2:1 to Glofit-GemOx or rituximab-GemOx (R-GemOx). ctDNA was analyzed using the AVENIO Oncology Assay NHL test and a customized linked somatic variants method, where co-occurring somatic variants 175 base pairs apart on single DNA fragments were identified. TMTV was assessed by fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT). Efficacy was assessed by PET-CT using Lugano criteria. Multivariate Kaplan-Meier and Cox-regression analyses were inverse probability weighting-adjusted to account for potential sampling bias in the biomarker-evaluable population. All pts provided written informed consent. Results As of May 1, 2025, among TMTV-evaluable pts (n=246), high baseline TMTV (>=125cm3, median) was prognostic for inferior PFS (hazard ratio [HR], 1.49, p=0.004). Glofit-GemOx showed improved PFS over R-GemOx irrespective of TMTV burden (high TMTV: HR, 0.37, p<0.001; low TMTV: HR, 0.30, p<0.001). Among ctDNA-evaluable pts (n=161), higher baseline ctDNA (>=200 mutant molecules/mL, median) was associated with inferior PFS (HR, 1.68, p=0.001). Glofit-GemOx demonstrated improved PFS over R-GemOx across subgroups with both high (HR, 0.51, p=0.024) and low (HR, 0.28, p=0.002) ctDNA. Among 144 pts with both biomarkers, a combined TMTV/ctDNA analysis yielded superior prognostic stratification compared with either biomarker alone. Longitudinal ctDNA analyses showed higher rates of undetected ctDNA with Glofit-GemOx vs R-GemOx across all timepoints: 47.7% vs 9.5% at Days 25-65 (early treatment), 65.6% vs 32.1% at Days 65-110 (mid-treatment), and 70.0% vs 31.6% at Days 110-220 (Figure). Among pts treated with Glofit-GemOx, undetected ctDNA status at Cycle 3 was strongly associated with prolonged PFS (p<0.001) and showed greater prognostic value vs PET-CT-assessed complete response (CR) at Cycle 4 (24-month PFS difference: 60% by ctDNA status [detected vs undetected]; 25% by PET-CT [CR vs non-CR]). Similarly, at the end of treatment, undetected ctDNA status was a prognostic indicator of long-term outcomes, with a 24-month PFS of 81% vs 30% for pts with undetected vs detected ctDNA, respectively. Summary/Conclusion These results demonstrate the potential for TMTV and ctDNA as powerful prognostic tools in R/R DLBCL. Glofit-GemOx demonstrated superior efficacy over R-GemOx regardless of tumor burden (TMTV or ctDNA). In addition, longitudinal ctDNA monitoring supports early response assessment, with undetected ctDNA status by Cycle 3 emerging as a strong predictor of long-term PFS. Higher rates of undetectable ctDNA were observed with Glofit-GemOx vs R-GemOx, validating its clinical benefit and supporting the superior efficacy observed in the primary analysis of STARGLO. (Figure Presented)