National Cancer Institute, Center for Cancer Research, Bethesda, Maryland.
National Cancer Center Hospital East, Kashiwa, Japan.
JAMA Oncol. 2023 Dec 1;9(12):1669-1677. doi: 10.1001/jamaoncol.2023.4025.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
患有复发性小细胞肺癌（SCLC）的患者具有较差的预后和较少的治疗选择，SCLC 是一种高复制应激肿瘤。一项 2 期研究表明，在拓扑替康中加入共济失调毛细血管扩张症和 Rad3 相关激酶抑制剂贝佐司替布具有抗肿瘤活性。
研究贝佐司替布联合拓扑替康是否改善复发性 SCLC 患者的临床结局。
设计、地点和参与者：2019 年 12 月 1 日至 2022 年 12 月 31 日期间，这项开放标签的 2 期随机临床试验在 16 家美国癌症中心招募了 60 名患有 SCLC 且在 1 次或多次先前治疗后复发的患者。先前接受过拓扑替康治疗的患者不符合条件。
符合条件的患者被随机分配接受拓扑替康单药治疗（第 1 组），1.25 mg/m2 静脉滴注，第 1 至 5 天；或接受贝佐司替布（第 2 组），210 mg/m2 静脉滴注，第 2 天和第 5 天，21 天为一个周期。根据一线铂类化疗药物对肿瘤的敏感性进行分层随机分组。
主要终点是在意向治疗人群中的无进展生存期（PFS）。次要终点包括总生存期（OS）在总体人群和铂敏感或铂耐药肿瘤患者中的情况。每个治疗组的 PFS 和 OS 采用 Kaplan-Meier 法进行估计。采用对数秩检验比较两组的 PFS 和 OS，采用 Cox 比例风险模型估计治疗风险比（HR）及其相应的 95%双侧置信区间（CI）。
这项研究共纳入 60 名患者（中位数[范围]年龄，59[34-79]岁；33[55%]为男性），其中 20 名随机分配接受拓扑替康单药治疗，40 名接受拓扑替康联合贝佐司替布治疗。中位（IQR）随访 21.3（18.1-28.3）个月后，两组间 PFS 无差异（第 1 组的中位 PFS 为 3.0[95%CI，1.2-5.1]个月，第 2 组为 3.9[95%CI，2.8-4.6]个月；HR，0.80[95%CI，0.46-1.41]；P=0.44）。联合治疗的总生存期显著延长（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=0.03）。两组的不良事件谱相似（例如，3 级或 4 级血小板减少症，20 名[55%] vs 40 名[50%]，任何等级的恶心，9 名[45%] vs 14 名[35%]）。
在这项随机临床试验中，与拓扑替康单药治疗相比，贝佐司替布联合拓扑替康治疗未能改善复发性 SCLC 患者的 PFS。然而，联合治疗显著改善了 OS。
ClinicalTrials.gov 标识符：NCT03896503。
