Department of Radiation Oncology, University of Alabama at Birmingham, USA.
Department of Radiotherapy, Gustave Roussy, INSERM1030 radiothérapie moléculaire, Université Paris-Saclay, Villejuif, France.
Radiother Oncol. 2021 Apr;157:203-209. doi: 10.1016/j.radonc.2021.01.032. Epub 2021 Feb 9.
This study explored the feasibility of safely combining prexasertib, with cisplatin-radiotherapy (Part A) or cetuximab-radiotherapy (Part B) in patients with previously untreated, locoregionally advanced head and neck squamous cell carcinoma (HNSCC).
Escalating doses of prexasertib were administered in each combination using a modified Time-to-Event Continual Reassessment Method. Pharmacokinetic (PK) analysis was performed using standard non-compartmental methods of analysis. Antitumor activity was evaluated using RECIST version 1.1.
In Part A, 7 patients received 20 mg/m prexasertib and cisplatin-radiotherapy. This dose exceeded the maximum tolerated dose (MTD); no other prexasertib dose was assessed. In Part B, 18 patients received prexasertib (20-40 mg/m) and cetuximab-radiotherapy. The 30 mg/m dose of prexasertib was determined as the MTD. Febrile neutropenia was the dose-limiting toxicity in each arm. Most common treatment-emergent adverse events with both combinations were neutropenia, thrombocytopenia, dysphagia, stomatitis, dry mouth, anemia, radiation skin injury [reported term radiation dermatitis], and nausea. PK of prexasertib was consistent with previously published data following prexasertib monotherapy. Overall response rate in Parts A and B was 71.4% and 83.3%, respectively. The small number of patients and follow-up limits the interpretation of efficacy data.
This study did not establish a safe dose of cisplatin-radiotherapy. However, it demonstrates the proof-of-principle that prexasertib could be safely combined with cetuximab-radiotherapy. These data will provide the basis to leverage the potential radio-sensitization properties of a CHK1 inhibitor in combination with radiation or other targeted agents in a variety of therapeutic settings.
本研究旨在探索在未经治疗的局部晚期头颈部鳞状细胞癌（HNSCC）患者中，将 prexasertib 与顺铂放疗（A 部分）或西妥昔单抗放疗（B 部分）联合应用的安全性。
采用改良的时间事件连续评估方法（Time-to-Event Continual Reassessment Method），对递增剂量的 prexasertib 进行联合用药。采用标准非房室分析方法进行药代动力学（PK）分析。采用 RECIST 版本 1.1 评价抗肿瘤活性。
在 A 部分，7 例患者接受了 20mg/m2 的 prexasertib 和顺铂放疗。该剂量超过了最大耐受剂量（MTD）；未评估其他 prexasertib 剂量。在 B 部分，18 例患者接受了 prexasertib（20-40mg/m2）和西妥昔单抗放疗。30mg/m2 的 prexasertib 剂量被确定为 MTD。发热性中性粒细胞减少症是每个治疗组的剂量限制毒性。两种联合治疗最常见的治疗相关不良事件是中性粒细胞减少症、血小板减少症、吞咽困难、口炎、口干、贫血、放射性皮肤损伤（报告术语为放射性皮炎）和恶心。prexasertib 的 PK 与 prexasertib 单药治疗的先前数据一致。A 部分和 B 部分的总缓解率分别为 71.4%和 83.3%。由于患者数量少和随访时间限制，疗效数据的解释有限。
本研究未确定顺铂放疗的安全剂量。然而，它证明了一个原则，即 prexasertib 可以与西妥昔单抗放疗安全联合。这些数据将为利用 CHK1 抑制剂的潜在放射增敏特性提供基础，在各种治疗环境中与放射治疗或其他靶向药物联合应用。
