Tucidinostat plus R-CHOP in untreated MYC/BCL2 double-expressor diffuse large B-cell lymphoma：topline efficacy and safety results from the randomized phase 3 DEB study

Abstract INTRODUCTION Epigenetic dysregulation is frequently associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). Tucidinostat (formerly known as chidamide), a subtype-selective histone deacetylase (HDAC) inhibitor, exerts epigenetic modulation of aberrant gene expression, a hallmark of various malignancies. Phase 2 studies suggest that tucidinostat combined with R-CHOP (CR-CHOP) has promising activity in double-expressor lymphoma (DEL), a subtype characterized by MYC and BCL2 co-expression that is historically associated with poor clinical outcomes. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3 trial (DEB) to evaluate the efficacy and safety of tucidinostat plus R-CHOP in comparison with R-CHOP in previously untreated DEL patients. Patients were randomly assigned in a 1:1 ratio to receive 20 mg oral tucidinostat or matching placebo plus six cycles of R-CHOP. Patients who had complete response (CR) after combination therapy received either tucidinostat or placebo treatment, with a maximum duration of 24 weeks. The primary end point was investigator-assessed event-free survival (EFS). Secondary end points included CR rate evaluated at the end of combination treatment, progression-free survival (PFS), disease-free survival (DFS), overall survival (OS) and safety. RESULTS A total of 423 patients were enrolled and randomized, with 211 assigned to the tucidinostat group and 212 to the placebo group. At the data cutoff date (June 26, 2025), with a median follow-up of 44.9 months (95%CI, 43.8-46.6), patients receiving tucidinostat plus R-CHOP had significantly improved EFS compared with those receiving placebo plus R-CHOP. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after CR, death, or initiation of new therapy for residual disease (stratified hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.54 to 0.96; P=0.02). EFS rates favored tucidinostat at 2 years (60.3% vs 50.5%) and 3 years (56.8% vs 47.7%). The CR rate at the end of combination treatment was 73.0% (95% CI, 66.6-78.5) in the tucidinostat group versus 61.8% (95% CI, 55.1-68.1) in the placebo group, with an adjusted between-group difference of 11.1% (95% CI, 2.3-20.0; P=0.01). Overall, the tucidinostat plus R-CHOP regimen demonstrated a generally well tolerated safety profile, consistent with the known toxicity patterns of the individual agents. The incidence of ≥ grade 3 hematologic adverse events was generally higher in the tucidinostat group than the placebo group, but most patients were able to tolerate and complete the planned treatment cycles. No significant cardiac toxicity, hepatotoxicity, or nephrotoxicity were observed in both groups. CONCLUSION In previously untreated patients with DEL, the addition of tucidinostat to R-CHOP significantly improved EFS and increased the CR rate compared with R-CHOP alone, with no unexpected safety concerns. (Funded by Shenzhen Chipscreen Biosciences; ClinicalTrials.gov number, NCT04231448).