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Abstract：
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.
摘要：
Fimepinostat(CUDC-907),一类组蛋白去乙酰化酶和磷脂酰肌醇3-激酶的口服小分子抑制剂，在复发/难治性（R/R）弥漫性大型和高级别B细胞淋巴瘤（DLBCL/HGBL）患者的1期研究中证明了疗效，特别是那些MYC蛋白表达和/或MYC基因重排/拷贝数增加（MYC改变的疾病）。因此,我们在该患者人群中进行了一项2期Fimepinostat研究,纳入了66例符合条件的患者.MYC-IHC≥40％（n=46）的患者的总反应（OR）率的主要终点为15％。随后，我们进行了探索性汇总分析,包括在1期和2期研究中接受治疗的患者,这些患者基于是否存在MYC改变的疾病以及通过富集调节子分析(VIPER)对蛋白质活性进行虚拟推断鉴定的生物标志物.对于这些患有MYC改变疾病的患者(n=63)，总体反应（OR）率为22％，其中7名反应患者仍在治疗约两年或更长时间，VIPER产生了三蛋白生物标志物分类，阳性和阴性预测值≥85%。MYC改变的R/RDLBCL/HGBL患者接受单药fimetinostat治疗，可以延长反应持续时间。组合疗法和/或基于生物标志物的患者选择策略可以在未来的临床试验中导致更高的应答率。
