Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2023 Jul 15;129(14):2201-2213. doi: 10.1002/cncr.34773. Epub 2023 Apr 4.
Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination.
The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort.
Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing).
Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients.
Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.
Selinexor（KPT-330）是一种有效的 exportin 1（XPO1）抑制剂，可抑制肿瘤生长。Selinexor 在体外和体内增强了厄瑞布林在三阴性乳腺癌（TNBC）中的抗肿瘤疗效。鉴于 TNBC 和肉瘤的未满足的医疗需求，作者探索了这种联合治疗的安全性和疗效。
作者使用 3+3 剂量递增设计，对接受过晚期实体瘤治疗的患者和 TNBC 患者进行了 selinexor 和 eribulin 联合治疗的 1b 期试验。
19 名 TNBC 患者、9 名肉瘤患者和 3 名其他癌症患者被纳入剂量递增队列（n=10）和剂量扩展队列（n=21）。中位治疗线数为 4 条（范围为 1 至 7 条）。Selinexor 最常见的治疗相关不良事件为恶心（77%）、白细胞减少（77%）、贫血（68%）、中性粒细胞减少（68%）和疲劳（48%）。在第一剂量水平时发生了一例剂量限制毒性，表现为持续的 3 级中性粒细胞减少症。推荐的 2 期剂量为每周口服 80mg selinexor 和每 3 周静脉注射 1mg/m eribulin，第 1 和 8 天各一次。在 3 名患者中观察到客观缓解率（ORR）为 10%。在剂量递增队列中，ORR 为 10%，而 6 名患者病情稳定。在 TNBC 剂量扩展队列（n=18）中，ORR 为 11%，其中 2 名患者有确认的部分缓解，缓解持续时间分别为 10.8 个月和 19.1 个月（持续）。
Selinexor 和 eribulin 具有可接受的毒性特征和适度的总体疗效，在某些患者中可产生持久的缓解。
