Ifupinostat achieved a 36.5% response rate in relapsed or refractory DLBCL, but median PFS was 2.7 months, with substantial hematologic toxicity.
Written By: Mayuresh Salvi, PharmD
Reviewed By: Pharmacally Editorial Team
A multicenter phase 2 study published in Signal Transduction and Targeted Therapy reported an objective response rate (ORR) of 36.5% with ifupinostat in patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) who had received at least two prior lines of systemic therapy. However, median progression-free survival (PFS) was 2.7 months, highlighting the difference between achieving a response and maintaining disease control. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 86.7% of patients.
Ifupinostat (BEBT-908) is an intravenous dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase alpha (PI3Kα). China granted the drug conditional approval on June 30, 2025, as monotherapy for adults with r/r DLBCL after at least two lines of systemic therapy, pending confirmatory clinical evidence.
Phase 2 Study Design
The single-arm study enrolled patients across 28 hospitals in China between June 2020 and July 2022. Investigators administered intravenous ifupinostat at 22.5 mg/m² on days 1, 3, 5, 8, 10 and 12 of each 21-day cycle. The primary endpoint was ORR assessed by blinded independent central review.
Of 128 patients included in the safety population, 115 were evaluable for efficacy. Median follow-up was 19.58 months, with the primary analysis based on a July 2023 data cutoff.
Responses Did Not Translate into Prolonged Disease Control
The ORR was 36.5% (42/115; 95% confidence interval [CI], 27.7–46.0), including a complete response rate of 11.3% (13/115). The disease control rate was 60.0% (69/115), incorporating patients with stable disease as well as objective responses.
Median duration of response was 6.2 months (95% CI, 3.5–14.5). Median PFS was 2.7 months (95% CI, 1.6–3.7), while median overall survival (OS) was 9.9 months (95% CI, 7.8–14.8). At 12 months, the PFS rate was 16.6% and the OS rate was 45.3%.
Patients who achieved complete or partial responses had a median PFS of 8.1 months and median OS of 25.6 months. These responder-specific outcomes suggest that patients who benefit initially may experience more durable disease control. However, they describe a selected subgroup and should not be interpreted as expected outcomes for the overall treated population.
Exploratory analyses also reported responses in four of five patients who progressed after autologous stem cell transplantation, two of two after bispecific antibody treatment, and four of six after CAR-T therapy. The small sample sizes prevent reliable conclusions about efficacy following these treatments.
Hematologic Toxicity Was Substantial
TRAEs occurred in 99.2% of patients (127/128), and 86.7% experienced grade 3 or higher TRAEs. Severe thrombocytopenia was the most frequent high-grade toxicity, affecting 75.8% of patients (97/128), followed by neutropenia in 33.6% and leukopenia in 22.7%.
Serious TRAEs occurred in 31.3% of patients. Thrombocytopenia was the most common serious treatment-related event, affecting 21.1%. Median recovery time from thrombocytopenia was 15 days. No treatment-related deaths were reported.
Although the investigators characterized the safety profile as manageable, the frequency of severe cytopenias represents a substantial treatment burden. The findings underscore the importance of hematologic monitoring, supportive care and appropriate treatment modifications.
Approval and Confirmatory Evidence
The phase 2 study evaluated ifupinostat at 22.5 mg/m², whereas the Drugs first-approval report lists an approved Chinese regimen of 18.5 mg/m² on the same dosing schedule. The efficacy and safety findings from the study dose should not automatically be assumed to apply identically to the approved regimen.
Separate evidence from an exploratory phase 1b study of ifupinostat plus rituximab reported an ORR of 76.2% among 21 evaluable patients. These preliminary combination results are not directly comparable with the monotherapy findings because the treatment regimens and study populations differ.
A randomized phase 3 study (NCT06792253) is evaluating ifupinostat plus rituximab against investigator-selected standard chemotherapy regimens, including R-GemOx or R-ICE. The study is intended to provide comparative evidence that the single-arm phase 2 trial cannot establish.
Clinical Interpretation
Ifupinostat demonstrated antitumor activity in heavily pretreated r/r DLBCL, but the 36.5% ORR must be considered alongside a median PFS of 2.7 months and substantial hematologic toxicity. The single-arm design also prevents conclusions about superiority over available treatments. Confirmatory evidence will be important in determining the treatment’s comparative benefit and the clinical relevance of its observed responses.
References
Shi, Y., Liu, P., Li, Y. et al. Efficacy and safety of ifupinostat in relapsed or refractory diffuse large B-cell lymphoma: a multicenter, single-arm phase 2 study. Sig Transduct Target Ther 11, 466 (2026). https://doi.org/10.1038/s41392-026-02926-8
Study of BEBT-908 Combined with Drugs in the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma, ClinicalTrials.gov ID NCT06164327
Study Comparing BEBT-908 Combined with R to SOC for the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma, ClinicalTrials.gov ID NCT06792253
About the Writer
Mayuresh Sunil Salvi (Linkedin) is a PharmD professional and healthcare writer with a strong interest in pharmacovigilance, drug safety, and emerging medical research. He is passionate about exploring new drug discoveries, clinical research, and advances in evidence-based medicine. His interests also include ward rounds, prescription audits, and treatment analysis to support rational pharmacotherapy and improved patient care.