Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA.
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center-Hillman Cancer Center, Pittsburgh, PA, USA.
Oncologist. 2023 Nov 2;28(11):1007-e1107. doi: 10.1093/oncolo/oyad221.
CREBBP and EP300 mutations occur at a frequency of 15% and 13%, respectively, in small cell lung cancer (SCLC), and preclinical models demonstrated susceptibility to targeting with HDAC inhibitors.
Patients with treatment-naïve extensive-stage SCLC, ECOG ≤2 were enrolled and treated with entinostat orally weekly (4 dose levels, DL) in combination with standard dose carboplatin, etoposide, and atezolizumab. Cohort allocation was determined by Bayesian optimal interval (BOIN) design targeting an MTD with a DLT rate of 20%.
Three patients were enrolled and treated at DL1 with entinostat 2 mg. Patients were aged 69-83; 2 male, 1 female; 2 were ECOG 1, and 1 was ECOG 0. The most common adverse events (AEs) were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), and hypocalcemia (2). Two experienced DLTs during cycle 1: (1) grade (Gr) 4 febrile neutropenia, and (1) Gr 5 sepsis. BOIN design required stopping accrual to DL1, and the trial was closed to further accrual. Entinostat and atezolizumab pharmacokinetics were both comparable to historical controls.
Addition of entinostat to atezolizumab, carboplatin, and etoposide is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia. Further exploration of entinostat with carboplatin, etoposide, and atezolizumab should not be explored. (ClinicalTrials.gov Identifier: NCT04631029).
在小细胞肺癌（SCLC）中，CREBBP 和 EP300 突变的频率分别为 15%和 13%，临床前模型显示对 HDAC 抑制剂具有敏感性。
入组未经治疗的广泛期 SCLC 患者，ECOG 评分为 2 分及以下，接受每周口服恩替诺特（4 个剂量水平，DL）联合标准剂量卡铂、依托泊苷和阿替利珠单抗治疗。采用贝叶斯最优区间（BOIN）设计，根据 DLT 率为 20%确定目标最大耐受剂量（MTD）进行分组。
3 例患者接受恩替诺特 2mg 治疗，入组 DL1。患者年龄 69-83 岁；2 例男性，1 例女性；2 例 ECOG 评分为 1，1 例为 ECOG 评分为 0。最常见的不良反应（AE）为贫血（3 例）、中性粒细胞减少症（3 例）、血小板减少症（2 例）、白细胞减少症（2 例）和低钙血症（2 例）。2 例患者在第 1 周期出现 DLT：（1）4 级发热性中性粒细胞减少症，（1）5 级脓毒症。BOIN 设计要求停止入组 DL1，试验关闭进一步入组。恩替诺特和阿替利珠单抗的药代动力学均与历史对照相似。
在阿替利珠单抗、卡铂和依托泊苷的基础上加用恩替诺特不安全，导致中性粒细胞减少症、血小板减少症早期且严重。不应进一步探索恩替诺特联合卡铂、依托泊苷和阿替利珠单抗。（临床试验标识符：NCT04631029）
