The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sarah Cannon Research Institute, Nashville, Tennessee.
Clin Cancer Res. 2018 Jul 15;24(14):3263-3272. doi: 10.1158/1078-0432.CCR-17-3347. Epub 2018 Apr 11.
Prexasertib, a checkpoint kinase 1 inhibitor, demonstrated single-agent activity in patients with advanced squamous cell carcinoma (SCC) in the dose-escalation portion of a phase I study (NCT01115790). Monotherapy prexasertib was further evaluated in patients with advanced SCC. Patients were given prexasertib 105 mg/m as a 1-hour infusion on day 1 of a 14-day cycle. Expansion cohorts were defined by tumor and treatment line. Safety, tolerability, efficacy, and exploratory biomarkers were analyzed. Prexasertib was given to 101 patients, including 26 with SCC of the anus, 57 with SCC of the head and neck (SCCHN), and 16 with squamous cell non-small cell lung cancer (sqNSCLC). Patients were heavily pretreated (49% ≥3 prior regimens). The most common treatment-related adverse event was grade 4 neutropenia (71%); 12% of patients had febrile neutropenia. Median progression-free survival was 2.8 months [90% confidence interval (CI), 1.9-4.2] for SCC of the anus, 1.6 months (90% CI, 1.4-2.8) for SCCHN, and 3.0 months (90% CI, 1.4-3.9) for sqNSCLC. The clinical benefit rate at 3 months (complete response + partial response + stable disease) across tumors was 29% (23% SCC of the anus, 28% SCCHN, 44% sqNSCLC). Four patients with SCC of the anus had partial or complete response [overall response rate (ORR) = 15%], and three patients with SCCHN had partial response (ORR = 5%). Biomarker analyses focused on genes that altered DNA damage response or increased replication stress. Prexasertib demonstrated an acceptable safety profile and single-agent activity in patients with advanced SCC. The prexasertib maximum-tolerated dose of 105 mg/m was confirmed as the recommended phase II dose. .
普雷萨替尼是一种检查点激酶 1 抑制剂，在 I 期研究的剂量递增部分，该药在晚期鳞状细胞癌（SCC）患者中表现出单药活性（NCT01115790）。普雷萨替尼单药治疗进一步在晚期 SCC 患者中进行了评估。患者接受 105mg/m2普雷萨替尼静脉输注 1 小时，每 14 天为一个周期，用药 1 天。扩展队列根据肿瘤和治疗线进行定义。分析了安全性、耐受性、疗效和探索性生物标志物。101 例患者接受了普雷萨替尼治疗，其中包括 26 例肛门 SCC、57 例头颈部 SCC（SCCHN）和 16 例鳞状非小细胞肺癌（sqNSCLC）。患者接受了大量预处理（49%的患者接受过≥3 种方案治疗）。最常见的治疗相关不良事件是 4 级中性粒细胞减少症（71%）；12%的患者发生发热性中性粒细胞减少症。肛门 SCC 的中位无进展生存期为 2.8 个月[90%置信区间（CI），1.9-4.2]，SCCHN 为 1.6 个月（90%CI，1.4-2.8），sqNSCLC 为 3.0 个月（90%CI，1.4-3.9）。在所有肿瘤中，3 个月时的临床获益率（完全缓解+部分缓解+疾病稳定）为 29%（肛门 SCC 为 23%，SCCHN 为 28%，sqNSCLC 为 44%）。4 例肛门 SCC 患者有部分或完全缓解[总缓解率（ORR）=15%]，3 例 SCCHN 患者有部分缓解（ORR=5%）。生物标志物分析集中在改变 DNA 损伤反应或增加复制应激的基因上。普雷萨替尼在晚期 SCC 患者中表现出可接受的安全性和单药活性。105mg/m2 普雷萨替尼的最大耐受剂量被确认为推荐的 II 期剂量。
