The University of Texas MD Anderson Cancer Center, Houston, Texas.
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Clin Cancer Res. 2021 Apr 1;27(7):1864-1874. doi: 10.1158/1078-0432.CCR-20-3242. Epub 2021 Jan 25.
Prexasertib, a checkpoint kinase 1 inhibitor (CHK1), exhibited modest monotherapy antitumor activity in previous studies. Preclinical data were generated to support the clinical combination of prexasertib + samotolisib, a PI3K/mTOR inhibitor.
Prexasertib + samotolisib was first evaluated in triple-negative breast cancer (TNBC) cells, MDA-MB-231 orthotopic xenograft tumors, and TNBC patient-derived xenograft (PDX) mouse models. In the phase Ib trial, following dose escalation, the initial expansion arm (E1, solid tumors) explored prexasertib 105 mg/m intravenously every 14 days + samotolisib 200 mg orally twice daily. Subsequent expansion arms evaluated samotolisib 150 mg twice daily in patients carrying mutations (E2, solid tumors) or with TNBC (E3). Safety and antitumor activity were assessed.
Prexasertib + samotolisib inhibited cell proliferation in TNBC lines and primary tumor growth in the MDA-MB-231 model. Prexasertib + samotolisib exhibited synergistic or additive effects in 30 of 38 PDX single-mouse (" = 1") models, and provided rationale for clinical evaluation. In the phase Ib study, 53 patients were enrolled (escalation, = 13; E1, = 9; E2, = 15; and E3, = 16). No dose-limiting toxicities (DLT) were observed during escalation; however, DLT-equivalent toxicities were observed in E1, leading to samotolisib dose reduction (150 mg twice daily) in E2/E3. Common treatment-related adverse events were leukopenia/neutropenia (94.3%), thrombocytopenia (62.3%), and nausea (52.8%). During escalation, 2 patients achieved partial response for an overall response rate (ORR) of 15.4%, and ORRs were 13.3% for E2 () and 25% for E3 (TNBC).
Prexasertib + samotolisib showed antitumor activity in preclinical models and preliminary efficacy in heavily pretreated patients. The clinical combination was associated with toxicity, suggesting supportive measures may be required. However, these data may inform future trials using other CHK1 and PI3K pathway inhibitors.
先前的研究表明，细胞周期检查点激酶 1 抑制剂（CHK1）普雷沙替尼单药具有一定的抗肿瘤活性。生成了临床前数据以支持普雷沙替尼联合索拉非尼（PI3K/mTOR 抑制剂）的临床联合治疗。
首先在三阴性乳腺癌（TNBC）细胞、MDA-MB-231 原位异种移植肿瘤和 TNBC 患者来源异种移植（PDX）小鼠模型中评估普雷沙替尼+索拉非尼。在 Ib 期试验中，在剂量递增后，最初的扩展臂（E1，实体瘤）探索了普雷沙替尼 105 mg/m 静脉注射，每 14 天一次+索拉非尼 200 mg 口服，每日两次。随后的扩展臂评估了携带 突变的患者（E2，实体瘤）或 TNBC 患者（E3）中索拉非尼 150 mg 每日两次。评估了安全性和抗肿瘤活性。
普雷沙替尼+索拉非尼抑制了 TNBC 系细胞的增殖和 MDA-MB-231 模型中的原发性肿瘤生长。普雷沙替尼+索拉非尼在 38 个 PDX 单鼠模型中的 30 个模型中表现出协同或相加作用（ = 1），为临床评估提供了依据。在 Ib 期研究中，共入组了 53 例患者（递增组， = 13；E1 组， = 9；E2 组， = 15；E3 组， = 16）。在递增组中未观察到剂量限制毒性（DLT）；然而，E1 中观察到 DLT 等效毒性，导致 E2/E3 中索拉非尼剂量减少（150 mg 每日两次）。常见的治疗相关不良事件包括白细胞减少/中性粒细胞减少（94.3%）、血小板减少（62.3%）和恶心（52.8%）。在递增组中，有 2 例患者部分缓解，总缓解率（ORR）为 15.4%，E2 的 ORR 为 13.3%（ ），E3 的 ORR 为 25%（TNBC）。
普雷沙替尼+索拉非尼在临床前模型中显示出抗肿瘤活性，并在既往治疗过的患者中显示出初步疗效。该临床联合治疗与毒性相关，表明可能需要支持性治疗措施。然而，这些数据可能为未来使用其他 CHK1 和 PI3K 通路抑制剂的临床试验提供信息。
