Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, Florida.
Clin Cancer Res. 2019 Nov 15;25(22):6623-6632. doi: 10.1158/1078-0432.CCR-19-1305. Epub 2019 Aug 13.
Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may improve response to immune checkpoint inhibitors (ICIs). In a phase I/Ib trial, we tested the oral HDACi vorinostat combined with the programmed cell death protein 1 inhibitor pembrolizumab in advanced/metastatic non-small cell lung cancer.
Patients received intravenous pembrolizumab (200 mg every 3 weeks) plus oral vorinostat (200 or 400 mg/day). Primary endpoint was safety/tolerability. Secondary endpoints included response rate, progression-free survival, disease control rate (DCR), and overall survival. Tumor gene expression changes, T-cell density, and myeloid cell levels were studied in serial tissue specimens.
Thirty-three patients were treated (13 in phase I, 20 in phase Ib). In phase I, both ICI-naïve and ICI-pretreated patients were enrolled to determine dose-limiting toxicities (DLT). No DLTs were observed, and the recommended phase I dose was pembrolizumab 200 mg and vorinostat 400 mg. Any-grade adverse events were mainly fatigue (33%) and nausea/vomiting (27%). Of six ICI-naïve and 24 ICI-pretreated patients evaluable for response, four (13%) had partial response [two confirmed, one unconfirmed with subsequent prolonged stable disease (SD), one unconfirmed with subsequent progressive disease (PD)], 16 (53%) had SD, and 10 (33%) had PD for a DCR of 67%. In the ICI-pretreated cohort, three patients (one confirmed, two unconfirmed) had partial response and 10 had SD. Pretreatment CD8 T-cell presence in tumor stromal regions was associated with treatment benefit.
Pembrolizumab plus vorinostat was well tolerated and demonstrated preliminary antitumor activity despite progression on prior ICI treatment.
组蛋白去乙酰化酶抑制剂（HDACi）通过多种机制增强肿瘤免疫原性，可能提高免疫检查点抑制剂（ICI）的反应。在一项 I/ Ib 期试验中，我们测试了口服 HDACi 伏立诺他联合程序性细胞死亡蛋白 1 抑制剂帕博利珠单抗治疗晚期/转移性非小细胞肺癌。
患者接受静脉注射帕博利珠单抗（每 3 周 200mg）加口服伏立诺他（200 或 400mg/天）。主要终点是安全性/耐受性。次要终点包括缓解率、无进展生存期、疾病控制率（DCR）和总生存期。在连续的组织标本中研究了肿瘤基因表达变化、T 细胞密度和髓样细胞水平。
33 名患者接受了治疗（I 期 13 例，Ib 期 20 例）。在 I 期，入组了 ICI 初治和 ICI 预处理患者以确定剂量限制毒性（DLT）。未观察到 DLT，推荐的 I 期剂量为帕博利珠单抗 200mg 和伏立诺他 400mg。任何级别的不良事件主要是疲劳（33%）和恶心/呕吐（27%）。在可评估疗效的 6 例 ICI 初治和 24 例 ICI 预处理患者中，4 例（13%）有部分缓解[2 例为确认缓解，1 例为随后延长的稳定疾病（SD）的未确认缓解，1 例为随后进展的疾病（PD）的未确认缓解]，16 例（53%）有 SD，10 例（33%）有 PD，疾病控制率为 67%。在 ICI 预处理队列中，3 例（1 例确认，2 例未确认）有部分缓解，10 例有 SD。肿瘤基质区域中 CD8 T 细胞的存在与治疗获益相关。
尽管先前接受 ICI 治疗后进展，但帕博利珠单抗加伏立诺他联合治疗耐受性良好，并显示出初步的抗肿瘤活性。
