Purpose: Tuvusertib (M1774) is a potent, selective, orally administered ATR protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of tuvusertib monotherapy. Patients and Methods: Ascending tuvusertib doses were evaluated in 55 patients with metastatic or locally advanced unresectable solid tumors. A safety monitoring committee determined dose escalation based on PK, PD, and safety data guided by a Bayesian 2‑parameter logistic regression model. Molecular responses (MRs) were assessed in circulating tumor DNA samples. Results: Most common Grade ≥3 treatment-emergent adverse events were anemia (36%), neutropenia and lymphopenia (both 7%). Eleven patients experienced dose-limiting toxicities, most commonly Grade 2 (n=2) or Grade 3 (n=8) anemia. No persistent effects on blood immune cell populations were observed. The RDE was 180mg tuvusertib QD, 2 weeks on/1 week off, which was better tolerated than the MTD (180mg QD continuously). Tuvusertib median time to peak plasma concentration ranged from 0.5–3.5h and mean elimination half-life from 1.2–5.6h. Exposure-related PD analysis suggested maximum target engagement at ≥130mg tuvusertib QD. Tuvusertib induced frequent MRs in the predicted efficacious dose range, MRs were enriched in patients with radiological disease stabilization and complete MRs were detected for mutations in ARID1A, ATRX and DAXX. One patient with platinum- and PARP inhibitor‑resistant BRCA wild-type ovarian cancer achieved an unconfirmed RECIST v1.1 partial response. Conclusions: Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

中文翻译：

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共济失调毛细血管扩张症和 Rad3 相关 (ATR) 抑制剂 Tuvusertib (M1774) 作为实体瘤患者单一疗法的首次人体研究

用途：Tuvusertib (M1774) 是一种有效的、选择性的、口服 ATR 蛋白激酶抑制剂。这项首次人体研究 (NCT04170153) 评估了 tuvusertib 单药治疗的安全性、耐受性、最大耐受剂量 (MTD)、推荐扩展剂量 (RDE)、药代动力学 (PK)、药效学 (PD) 和初步疗效。患者和方法：在 55 名患有转移性或局部晚期不可切除实体瘤的患者中评估了递增的 tuvusertib 剂量。安全监测委员会根据 PK、PD 和贝叶斯 2 参数逻辑回归模型指导的安全数据确定剂量递增。在循环肿瘤 DNA 样本中评估分子反应 (MR)。结果：最常见的 ≥3 级治疗引起的不良事件是贫血（36%）、中性粒细胞减少和淋巴细胞减少（均为 7%）。11 名患者经历了剂量限制性毒性，最常见的是 2 级 (n=2) 或 3 级 (n=8) 贫血。没有观察到对血液免疫细胞群的持续影响。RDE 为 180mg tuvusertib QD，用药 2 周/停药 1 周，比 MTD（连续 180mg QD）耐受性更好。Tuvusertib 达到血浆峰浓度的中位时间为 0.5-3.5 小时，平均消除半衰期为 1.2-5.6 小时。暴露相关的 PD 分析表明，≥130mg tuvusertib QD 时的最大靶标参与度。Tuvusertib 在预测的有效剂量范围内诱导频繁的 MR，MR 在放射学疾病稳定的患者中丰富，并且在 ARID1A、ATRX 和 DAXX 突变中检测到完整的 MR。一名对铂类和 PARP 抑制剂耐药的 BRCA 野生型卵巢癌患者取得了未经证实的 RECIST v1.1 部分缓解。结论：Tuvusertib 表现出可控的安全性和与暴露相关的目标参与度。tuvusertib 的进一步临床评估正在进行中。