Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Cancer. 2023 Sep 1;129(17):2685-2693. doi: 10.1002/cncr.34820. Epub 2023 May 2.
In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC).
The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration.
A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4 months (95% CI, 3.4-19.8 months) and 3.0 months (95% CI, 1.7-5.7 months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%.
Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed.
ClinicalTrials.gov identifier: NCT02419495.
New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer.
在肺癌中，核输出蛋白的过度表达会导致关键肿瘤抑制蛋白和细胞周期调节剂失活。选择性抑制核输出蛋白具有免疫调节活性。在这里，我们报告了 pembrolizumab 联合口服选择性核输出抑制剂 selinexor 治疗转移性非小细胞肺癌（mNSCLC）的临床安全性和早期疗效数据。
这项前瞻性研究者发起的研究的主要目的是确定 selinexor 联合 pembrolizumab 治疗 mNSCLC 患者的安全性和耐受性。次要目标包括确定客观肿瘤缓解率、疾病控制率和无进展生存期。
最终分析纳入了 17 例患者。15 例（88%）患者接受了超过两线的系统治疗，10 例（59%）患者有抗 PD-1/程序性死亡配体 1（PD-L1）治疗史。中位年龄为 67.5 岁。10 例患者发生与 selinexor 治疗相关的≥3 级不良事件。在接受过和未接受过抗 PD-1/PD-L1 治疗的患者以及有激活驱动突变的患者中均观察到治疗应答。中位总生存期和无进展生存期分别为 11.4 个月（95%CI，3.4-19.8 个月）和 3.0 个月（95%CI，1.7-5.7 个月）。总缓解率为 18%，6 个月疾病控制率为 24%。
Selinexor 联合 pembrolizumab 治疗 mNSCLC 具有有前景的抗肿瘤活性，包括那些接受过抗 PD-1/PD-L1 治疗的患者。治疗相关的毒性与这两种药物的既往安全性数据一致，未观察到重叠毒性。
NCT02419495。
正在研究预防或逆转免疫检查点抑制剂耐药的新策略。核输出蛋白的选择性抑制剂，如 selinexor，可以诱导肿瘤抑制途径的恢复，并诱导有效的免疫调节活性。本文包含了 pembrolizumab 联合 selinexor 治疗转移性非小细胞肺癌的临床安全性和早期疗效数据。
