Background: Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ATM, genes conferring replication stress (RS), or SDH. Methods: Patients were recruited to 4 cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient GIST. Patients were treated with berzosertib 240 mg/m2 IV twice per week. Pre and on-treatment biopsies were obtained in cohorts T1-T3. Results: Patients with SDH-mutant GIST had the longest median progression-free survival (PFS) (229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (g-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1-T3, increased expression of SFLN11 on treatment correlated with clinical benefit (HR = 0.045; 95%CI 0.005-0.400). Conclusions: Across cohorts, only SDH-mutant GIST patients experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

中文翻译：

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ATR 抑制剂 Berzosertib 作为单一疗法在四个分子定义的晚期实体瘤队列中的转化研究


背景： 临床前研究已经确定了对 ATR 抑制敏感性的分子相关性。这项转化研究旨在在携带 ATRX、ATM、赋予复制应激 （RS） 的基因或 SDH 改变的晚期实体瘤患者中测试 ATR 抑制剂 berzosertib。方法：将患者招募到 4 个队列： T1：ATRX 突变平滑肌肉瘤;T2： ATM 突变实体瘤;T3： RS 相关基因突变的实体瘤;和 T4： SDH 缺陷型 GIST。患者接受 berzosertib 240 mg/m2 静脉注射，每周 2 次。在 T1-T3 队列中获得治疗前和治疗中的活检。结果： SDH 突变 GIST 患者的中位无进展生存期 （PFS） 最长 （229 d），病情稳定为最佳反应。其他队列的患者在 4 个月内出现疾病进展。与有/无 ATM 或 RS 基因突变的患者相比，PFS 无显著差异。治疗活检中 pS345-CHK1 降低表明 berzosertib 与靶点结合，并伴有一部分患者的 DNA 损伤 （g-H2AX） 和 RS （pKAP1） 标志物水平显着增加。然而，这些生物标志物的变化并未转化为临床益处。相比之下，在 T1-T3 队列中，治疗中 SFLN11 表达增加与临床获益相关 （HR = 0.045;95% CI 0.005-0.400）。结论： 在队列中，只有 SDH 突变的 GIST 患者经历了长时间的疾病控制。尽管有证据表明靶点参与，但所有其他队列入组的患者 PFS 较短，表明快速适应 ATR 抑制剂单药治疗。在这些患者中，在 berzosertib 暴露期间表达 SLFN11 的肿瘤患者获得了最大的临床益处。