Tucidinostat plus R-CHOP in previously untreated diffuse large B-cell lymphoma with double expression of MYC and BCL2: An interim analysis from the phase III DEB study.

LBA7003 Background: Epigenetic dysregulation is commonly correlated with the pathogenesis and development in diffuse large B-cell lymphoma (DLBCL). Tucidinostat, a subtype-selective histone deacetylase (HDAC) inhibitor, has shown promising efficacy in combination with R-CHOP in DLBCL patients with double expression of MYC and BCL2 (DE) in exploratory studies. Methods: We conducted a randomized, double-blind, placebo-controlled, phase III trial (DEB) to evaluate the efficacy and safety of tucidinostat plus R-CHOP in comparison with R-CHOP in previously untreated DLBCL patients with DE. Patients were randomly assigned in a 1:1 ratio to receive six cycles of either tucidinostat plus R-CHOP (tucidinostat group) or placebo plus R-CHOP (placebo group). Patients who achieved complete response (CR) after combination therapy received either tucidinostat or placebo as maintenance treatment with a maximum duration of 24 weeks. The primary endpoint was investigator-assessed event-free survival (EFS), and the key secondary endpoint was the complete response rate (CRR) evaluated at the end of combination treatment. An interim analysis was pre-defined to be conducted when CRR was obtained and the number of EFS events reached at least 60% of the total events required for entire study. Results: Between May 21, 2020, and July 25, 2022, 423 patients were enrolled and randomly assigned, 211 to the tucidinostat group and 212 to the placebo group. At data cutoff of this interim analysis (January 10, 2023), the median follow-up time was 13.9 months (95% CI, 12.9 - 15.4). A total of 152 EFS events (68.5% of the planned total) were observed, with 64 (30.3%) in the tucidinostat group and 88 (41.5%) in the placebo group. The 24-month EFS rate was 58.9% (95% CI, 48.9-67.6) in the tucidinostat group and 46.2% (95% CI, 35.7-56.1) in the placebo group. The hazard ratio (HR) between the two groups was 0.68 (95% CI, 0.49-0.94), with a p-value of 0.018. At the completion of combination treatment, the CRR in the tucidinostat and placebo groups were 73.0% (95% CI, 66.6-78.5) and 61.8% (95% CI, 55.1-68.1), respectively. The adjusted difference in CRR was 11.1% (95% CI, 2.3-20.0; P=0.014). The safety profiles of both groups were as expected, with no new safety findings. 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: The DEB study is the first phase III trial to show that combining tucidinostat with R-CHOP regimen is a feasible and efficacious novel approach in previously untreated DLBCL patients with DE. Tucidinostat plus R-CHOP could be a new frontline treatment option in this patient population. Clinical trial information: NCT04231448 .