Tucidinostat Plus R-CHOP Improves EFS in DLBCL Expressing MYC and BCL2

Patients with previously untreated diffuse large B-cell lymphoma (DLBCL) expressing MYC and BCL2 (double-expressor [DE] lymphoma) treated with the combination of tucidinostat (chidamide) and R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisone) experienced an event-free survival (EFS) benefit vs those given R-CHOP plus placebo, according to an interim analysis of the phase 3 DEB study (NCT04231448) presented at the 2024 ASCO Annual Meeting.

“This study, DEB, is the first phase 3 study to confirm the benefit of R-CHOP plus epigenetic agents in previously untreated diffuse large B-cell lymphoma patients with stable expression of MTC and BCL2,” Weili Zhao, PhD, Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China, said during a presentation of the data. “…[This] combination regimen could be a new frontline treatment for patients.”

Safety and Efficacy of Tucidinostat

By the data cutoff of January 10, 2023, for the interim analysis, median follow-up was 13.9 months (range, 12.9-15.4), with a total of 152 EFS events observed, which accounted for 68.5% of the planned events of the study (n = 222).

This included 64 events (30.3%) in the tucidinostat group and 88 events (41.5%) in the placebo group (HR, 0.68; 95% CI, 0.49-0.94; P = .018). Further, the 24-month EFS rate with tucidinostat was 58.9% (95% CI, 48.9%-67.6%), compared with 46.2% (95% CI, 35.7%-56.1%) with placebo. Zhao noted that the prespecified subgroup analysis also showed a benefit in favor of tucidinostat use in combination with R-CHOP.

The complete response (CR) rate with the tucidinostat combination was 73.0% (95% CI, 66.6%-78.5%) vs 61.8% (95% CI, 55.1%-68.1%) with the placebo regimen, inferring an adjusted difference of 11.1% (95% CI, 2.3%-20.0%; P = .014). The prespecified subgroup analysis also favored tucidinostat.

Median progression-free survival (PFS) was not reached in either group; however, Zhao noted that it showed a potential prolongation trend. In total, 43 events occurred in the tucidinostat group, compared with 56 in the placebo arm (HR, 0.72; 95% CI, 0.49-1.08; P = .110). Further, the 24-month PFS rates were 67.3% (95% CI, 56.2%-76.2%) and 57.0% (95% CI, 44.2%-68.0%), respectively.

As of the cutoff date, overall survival (OS) events were limited and trends could not be determined, Zhao explained. Overall, 27 events occurred in the tucidinostat combination arm, compared with 31 events in the placebo arm (HR, 0.84; 95% CI, 0.50-1.40; P = .500), with 24-month OS rates of 82.8% (95% CI, 75.1-88.3%) and 76.5% (95% CI, 66.4%-84.0%), respectively.

Among hematologic adverse events (AEs), grade 3 or higher occurring with the tucidinostat regimen, vs placebo, included anemia (19.0% vs 9.9%, respectively), leukopenia (58.3% vs 44.8%), thrombocytopenia (25.1% vs 13.2%), neutropenia (60.2% vs 45.3%), and lymphopenia (33.6% vs 31.1%). Non-hematologic AEs of grade 3 or higher comprised hypokalemia (14.7% vs 5.2%, respectively) and pneumonia (15.6% vs 7.5%).

Serious AEs of all grades occurring in the tucidinostat and placebo arms comprised infectious pneumonia (16.1% vs 8.0%, respectively), bone marrow failure (15.6% vs 7.5%), febrile neutropenia (3.3% for both), interstitial lung disease (4.3% vs 3.8%), lung inflammation (4.3% vs 1.9%), leukopenia (3.8% vs 1.4%), thrombocytopenia (3.3% vs 0.9%), and neutropenia (2.4% vs 1.9%).

Unmet Need

“Approximately 30% of DLBCL patients exhibit co-expression of MYC and BCL2 proteins.… DE [lymphoma] belongs to a high-risk phenotypic entity with poor clinical outcomes, as 5-year [overall survival is] 30%,” Zhao explained, adding that the novel oral subtype-selective histone deacetylase inhibitor plus R-CHOP previously showed promising efficacy and safety in elderly patients with the disease.

Therefore, in the randomized double-blind, placebo-controlled, phase 3 study, investigators aimed to evaluate the efficacy and safety of tucidinostat plus R-CHOP, vs R-CHOP alone, in patients with previously untreated DLBCL with DE. Patients were randomly assigned 1:1 to receive either 6 cycles of tucidinostat plus R-CHOP (n = 211) or placebo plus R-CHOP (n = 212).

Patients who achieved CR after combination therapy received either tucidinostat or placebo as maintenance treatment with a maximum duration of 24 weeks.

Investigator-assessed EFS (defined as the time from randomization to the date of first documented disease progression, recurrence after CR, death from any cause, or initiation of new therapy for residual lesions after the end of therapy, whichever occurs first) served as the primary end point, while the secondary end point was CR rate evaluated at the end of combination treatment. Other secondary end points included disease-free survival, PFS, OS, and AEs.

Patients were stratified by International Prognostic Index (IPI) score (2 vs 3-5) and age (60 years or younger vs older than 60). Inclusion criteria included DLBCL with DE of MYC and BCL2, previously untreated, age 18 to 80 years, and an IPI score of >1.

Between May 21, 2020, and July 25, 2022, 423 patients were enrolled at 40 study centers in mainland China.

In total, 170 patients (80.6%) in the tucidinostat group and 165 patients (77.8%) in the placebo group completed all 6 cycles of combination treatment, with 64.0% and 52.4%, respectively, receiving maintenance therapy.

In the tucidinostat group, median age was 64 years (range, 55-68) and 43.1% were male, whereas the placebo group had a median age of 62 years (range, 54-67) and 51.9% were male. In the tucidinostat and placebo arms, the majority had an IPI score of 3-5 (55.0% vs 57.1%, respectively), and ECOG status of 0 or 1 (75.8% vs 75.5%), and elevated LDH (64.9% vs 68.4%).

Reference

Zhao W, Zhu J, Song Y, et al. 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. J Clin Oncol. 2024;42(suppl 17):LBA7003. doi:10.1200/JCO.2024.42.17_suppl.LBA7003