Kim Chul, Aggarwal Vanya, Daugaard Gedske, Tang Tianzhi, Ahn Jaeil, Besse Benjamin, Girard Nicolas, Giaccone Giuseppe, Petersen Peter Meidahl
Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia.
Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
JTO Clin Res Rep. 2025 May 15;6(9):100848. doi: 10.1016/j.jtocrr.2025.100848. eCollection 2025 Sep.
Thymic epithelial tumors (TETs) are rare and include thymomas (T) and thymic carcinomas (TC). Effective treatment options are needed for patients with progressive disease after platinum-based chemotherapy. Preclinical studies demonstrated antitumor activity of selinexor, an inhibitor of the nuclear receptor exportin-1 (XPO1/CRM1), supporting the clinical development of XPO1-targeted therapy for the treatment of TETs. To further assess the safety and efficacy of selinexor in TETs, we conducted two coordinated parallel phase II clinical trials.
This report includes two nearly identical phase II trials, designed to run in parallel, conducted in the United States (NCT03193437) and Europe (Denmark and France; NCT03466827). Analysis was performed on data pooled from both trials. Both trials were nonrandomized, open-label, two-armed phase II trials (arm A: thymoma, arm B: thymic carcinoma) with the same study design. Patients with histologically confirmed, advanced, inoperable TETs who had progressive disease after treatment with at least one platinum-containing chemotherapy regimen were included. In each 4-week cycle, patients received selinexor 60 mg twice weekly for 3 weeks. To improve tolerability, the starting dose was reduced to 40 mg twice weekly during the study. The primary objective was overall response rate (ORR) assessed by Response Evaluation Criteria in Solid Tumors 1.1, with secondary objectives including progression free survival (PFS), overall survival (OS), and adverse events (AEs) assessed per Common Terminology Criteria for Adverse Event version 4.03.
A total of 31 patients were enrolled between the two trials: 16 with T and 15 with TC. The median age was 57 (range: 41-81) years, with 17 men and 14 women. The median number of previous systemic therapies was 2 (range: 1-9). The starting dose was 60 mg twice weekly for 29 patients (93.5%) and 40 mg twice weekly for two patients (6.5%). There was one complete response in the TC group (ORR 6.7%; 95% confidence interval [CI]: 1.2%-29.8%) and two partial responses (ORR 12.5%; 95% CI: 3.5%-36.0%) in the T group. Stable disease as the best response was observed in 11 patients (68.6%) with T and 12 patients (80%) with TC. The median duration of selinexor therapy was 4.5 (range: 0.1-44.3) months. The most common treatment-related adverse events (TRAEs) were nausea (83.8%), vomiting (45.2%), anemia (41.9%), fatigue (38.7%), and asthenia (38.7%). The most common grade 3 or higher TRAEs were anemia (16.1%), thrombocytopenia (12.9%), and asthenia (12.9%). Furthermore, 20 patients (64.5%) required dose reductions due to AEs and 20 patients (64.5%) required dose interruptions. In the T group, the median PFS was 13.6 months (95% CI: 6.3-44.3), and the median OS was not reached. In the TC group, the median PFS was 7.8 months (95% CI: 4.3-15.5) and the median OS was 15.5 months (95% CI: 13.0-29.9). The trials were halted prematurely due to overall low ORRs and budgetary constraints.
Selinexor demonstrated modest anticancer activity in patients with pretreated advanced TETs. The treatment was complicated by high rates of TRAEs, leading to frequent dose reductions and interruptions.
胸腺上皮肿瘤（TETs）较为罕见，包括胸腺瘤（T）和胸腺癌（TC）。对于铂类化疗后病情进展的患者，需要有效的治疗方案。临床前研究表明，核受体输出蛋白1（XPO1/CRM1）抑制剂塞利尼索具有抗肿瘤活性，支持开展针对TETs的XPO1靶向治疗的临床研究。为进一步评估塞利尼索治疗TETs的安全性和疗效，我们开展了两项协调的平行II期临床试验。
本报告包括两项几乎相同的II期试验，设计为平行开展，分别在美国（NCT03193437）和欧洲（丹麦和法国；NCT03466827）进行。对两项试验汇总的数据进行分析。两项试验均为非随机、开放标签、双臂II期试验（A组：胸腺瘤，B组：胸腺癌），研究设计相同。纳入组织学确诊、晚期、无法手术切除且至少接受过一种含铂化疗方案治疗后病情进展的TETs患者。在每个4周周期中，患者每周两次接受60mg塞利尼索治疗，持续3周。为提高耐受性，研究期间起始剂量减至每周两次40mg。主要终点是根据实体瘤疗效评价标准1.1评估的总缓解率（ORR），次要终点包括无进展生存期（PFS）、总生存期（OS）以及根据不良事件通用术语标准4.03评估的不良事件（AE）。
两项试验共纳入31例患者：16例胸腺瘤患者和15例胸腺癌患者。中位年龄为57岁（范围：41 - 81岁），男性17例，女性14例。既往全身治疗的中位次数为2次（范围：1 - 9次）。29例患者（93.5%）起始剂量为每周两次60mg，2例患者（6.5%）起始剂量为每周两次40mg。胸腺癌组有1例完全缓解（ORR 6.7%；95%置信区间[CI]：1.2% - 29.8%），胸腺瘤组有2例部分缓解（ORR 12.5%；95% CI：3.5% - 36.0%）。胸腺瘤组11例患者（68.6%）和胸腺癌组12例患者（80%）的最佳疗效为疾病稳定。塞利尼索治疗的中位持续时间为4.5个月（范围：0.1 - 44.3个月）。最常见的治疗相关不良事件（TRAEs）为恶心（83.8%）、呕吐（45.2%）、贫血（41.9%）、疲劳（38.7%）和乏力（38.7%）。最常见的3级或更高等级TRAEs为贫血（16.1%）、血小板减少（12.9%）和乏力（12.9%）。此外，20例患者（64.5%）因AE需要减量，20例患者（64.5%）需要中断给药。胸腺瘤组中位PFS为13.6个月（95% CI：6.3 - 44.3），中位OS未达到。胸腺癌组中位PFS为7.8个月（95% CI：4.3 - 15.5），中位OS为15.5个月（95% CI：13.0 - 29.9）。由于总体ORR较低和预算限制，试验提前终止。
塞利尼索在预处理的晚期TETs患者中显示出适度的抗癌活性。该治疗因TRAEs发生率高而较为复杂，导致频繁减量和中断给药。
