Fimepinostat (CUDC‐907) in patients with relapsed/refractory diffuse large B cell and high‐grade B‐cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses

Abstract

Summary Fimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.

HDAC inhibitors with potential to overcome drug resistance in castration-resistant prostate cancer

“…CUDC-907 (fimepinostat) is another promising HDAC/kinase inhibitor, which was designed to target HDAC enzymes and the kinase PI3K [85] . [86] . More recently, a phase 2 study of oral CUDC-907 for the treatment of relapsed/refractory diffuse large and high-grade B-cell lymphoma (DLBCL and HGBL) patients with enhanced Myc-expression and/or altered MYC gene constitutions (e.g., altered gene composition by translocation) was published revealing an overall response rate of 22% in the MYC-altered disease patients [87] .…”

“…60% while no weight loss was detected [ 86 ] . More recently, a phase 2 study of oral CUDC-907 for the treatment of relapsed/refractory diffuse large and high-grade B-cell lymphoma (DLBCL and HGBL) patients with enhanced Myc-expression and/or altered MYC gene constitutions (e.g., altered gene composition by translocation) was published revealing an overall response rate of 22% in the MYC-altered disease patients [ 87 ] . Hence, patients enrolled for future prostate cancer clinical studies with oral CUDC-907 should be tested for their MYC-status.…”

Single Inhibitors versus Dual Inhibitors: Role of HDAC in Cancer

“…The phase I clinical trial of CUDC-101 was done against head and neck squamous cell carcinoma and showed good preclinical activity. The phase I and phase II studies of femepinostat (CUDC-907) were reported with relapsed/refractory diffuse large B cell and high-grade B-cell lymphoma. , The phase II study of the compound CUCD-907 gives encouraging results, and it has been approved by FDA for the treatment of relapsed or refractory DLBCL. A new kind of HDAC dual drug inhibitor EDO-S101, a combination of SAHA and bendamustine, inhibits both DNA and HDAC.…”

Targeting MYC-driven lymphoma: lessons learned and future directions

“…More advanced in their development, tucidinostat and fimepinostat (CUDC-907) have been or are being evaluated in Phase II/III trials (NCT02909777, NCT02674750). Zhang et al [64] showed improved 2-year progression-free survival (PFS) and overall survival (OS) in DEL patients, as well as a lessened negative prognostic impact of CREBBP/EP300 (Histone acetyltransferase p300) mutations when treated with tucidinostat in combination with R-CHOP. Furthermore, fimepinostat is a dual HDAC and PI3K inhibitor reported to have an objective response rate (ORR) of 15% in patients with relapsed/refractory DLBCL or HGBL with high MYC (≥ 40%).…”