Selinexor（KPT-330）是外搬运蛋白1（XPO1）的有效抑制剂，能够抑制肿瘤生长。Selinexor在体内和体外增强依利菌的三阴性乳腺癌抗肿瘤疗效。考虑到三阴性乳腺癌和肉瘤的无法满足医疗需求，作者探索了这种联合治疗的安全性和疗效。作者在患有晚期实体瘤和三阴性乳腺癌的患者中，使用3+3剂量递增设计进行了selinexor和依利菌的联合治疗1b期试验，并在剂量扩展队列中进行研究。包括三阴性乳腺癌（n=19），肉瘤（n=9）和其他癌症（n=3）在内的患者共10人参加了剂量递增队列和剂量扩展队列（n=21）。先前治疗的中位数行数为四次（该序列的先前行数范围为1次到7次）。selinexor的最常见治疗相关不良事件是恶心（77％），白细胞减少症（77％），贫血（68％），中性粒细胞减少症（68％）和疲劳（48％）。在第一剂量水平上出现了一个剂量限制性毒性，伴有持续的3级中性粒细胞减少症。推荐的2期剂量是每周口服80mg的selinexor和每3周的第1天和第8天静脉注射1mg/m² eribulin。三名患者的客观反应率（ORR）为10％。在剂量递增队列中，ORR为10％，而有6名患者的疾病得到了稳定。在TNBC剂量扩展队列（n =18）中，ORR为11％，有两个确认的部分反应持续时间分别为10.8和19.1个月（持续进行）。Selinexor和依利菌具有可接受的毒副作用和适度的总体疗效，并可对选择患者产生持久反应。对于晚期的三阴性乳腺癌和肉瘤，有效的治疗是一种未满足的需求。出口蛋白1与癌症相关蛋白的转运有关。临床前研究已经证明，接受selinexor和依利菌联合治疗的患者可以抑制肿瘤生长和提高肿瘤的敏感性。在这项1b期研究中，作者评估了口服出口蛋白1强效抑制剂selinexor和依利菌联合治疗在富含三阴性乳腺癌或肉瘤的晚期癌症患者中的安全性和临床活性。联合治疗良好耐受，大部分不良反应是轻微或中度的，可逆的，并会进行剂量调整或生长因子支持。 Selinexor和依利菌联合治疗产生了抗肿瘤反应，尤其是在一些三阴性乳腺癌患者中。该研究奠定了selinexor和依利菌在三阴性乳腺癌治疗中的前景和研究基础。 © 2023美国癌症协会。

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/m2 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.© 2023 American Cancer Society.