复发性小细胞肺癌（SCLC）是一种高复制应激肿瘤，患者预后较差，治疗选择很少。一项 2 期研究显示，在拓扑替康中添加共济失调性毛细血管扩张症和 Rad3 相关激酶抑制剂 berzosertib 具有抗肿瘤活性。研究在拓扑替康中添加 berzosertib 是否可以改善复发性 SCLC 患者的临床结果。2019 年 12 月 1 日至 12 月之间2022 年 12 月 31 日，这项开放标签 2 期随机临床试验从 16 个美国癌症中心招募了 60 名 SCLC 患者，这些患者在接受 1 种或多种既往治疗后复发。既往接受过拓扑替康治疗的患者不符合资格。符合条件的患者被随机分配接受单独的拓扑替康治疗（第 1 组），第 1 至 5 天静脉注射 1.25 mg/m2，或联合 berzosertib（第 2 组），第 2 天静脉注射 210 mg/m2 5 次，以 21 天为一个周期。随机分组根据肿瘤对一线铂类化疗的敏感性进行分层。主要终点是意向治疗人群的无进展生存期（PFS）。次要终点包括总体人群以及铂类敏感或铂类耐药肿瘤患者的总生存期（OS）。使用 Kaplan-Meier 方法估计每个治疗组的 PFS 和 OS。采用对数秩检验比较两组间的 PFS 和 OS，采用 Cox 比例风险模型估计治疗风险比 (HR) 和相应的双侧 95% CI。 60 名患者（中位数[范围] ] 年龄，59 [34-79] 岁；33 [55%] 男性）纳入本研究，其中 20 人被随机分配接受单独的拓扑替康治疗，40 人被随机分配接受拓扑替康与 berzosertib 的联合治疗。中位 (IQR) 随访 21.3 (18.1-28.3) 个月后，两组之间的 PFS 没有差异（中位 1 组为 3.0 [95% CI，1.2-5.1] 个月，第 1 组为 3.9 [95% CI] 个月。第 2 组的 CI，2.8-4.6] 个月；HR，0.80 [95% CI，0.46-1.41]；P = .44）。联合治疗的总生存期显着延长（5.4 [95% CI, 3.2-6.8] 个月 vs 8.9 [95% CI, 4.8-11.4] 个月；HR, 0.53 [95% CI, 0.29-0.96]，P = 。 03）。两组之间的不良事件概况相似（例如，3 级或 4 级血小板减少症，20 人中的 11 人 [55%] vs 40 人中的 20 人 [50%]，以及任何级别的恶心，20 人中的 9 人 [45%] vs 40 人中的 14 人[35%]）。在这项随机临床试验中，在复发性 SCLC 患者中，与单独使用拓扑替康治疗相比，使用 berzosertib 加拓扑替康治疗并未改善 PFS。然而，联合治疗显着改善了 OS.ClinicalTrials.gov 标识符：NCT03896503。

Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan.To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC.Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible.Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy.The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI.Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]).In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS.ClinicalTrials.gov Identifier: NCT03896503.