程序性细胞死亡蛋白 1 (PD-1) 抑制剂与化疗相比，可延长复发性/转移性头颈鳞状细胞癌 (R/M HNSCC) 的生存期，该癌通常表达细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 和程序性细胞死亡蛋白 1 (PD-1) 抑制剂。细胞死亡配体 1 (PD-L1)，为 PD-(L)1 和 CTLA-4 联合阻断提供了理论依据。我们报告了一项 PD-L1 抑制剂 durvalumab 加 CTLA-4 抑制剂 tremelimumab 的 I 期开放标签研究 (NCT02262741)。在剂量探索中，两组既往治疗的患者接受了 durvalumab 10 mg/kg 加 tremelimumab 3 mg/kg 的治疗，或 durvalumab 20 mg/kg 加 tremelimumab 1 mg/kg，最长 12 个月。剂量扩展包括两组先前未经治疗的 R/M HNSCC 患者，基线 PD-L1 肿瘤细胞 (TC) 表达≥25% 和 <25%，以及一组经过免疫治疗预处理的具有任何 PD-L1 水平的患者。所有患者均接受 durvalumab 20 mg/kg 加 tremelimumab 1 mg/kg，然后 durvalumab 10 mg/kg，疗程长达 12 个月。主要终点是安全性。次要终点是 RECIST 1.1 版的客观缓解率 (ORR)、药代动力学、药效学和免疫原性。共有 71 名患者接受治疗。 durvalumab 的中位暴露时间为 13.6 周，tremelimumab 的中位暴露时间为 13.1 周。在剂量探索中，没有发生剂量限制性毒性。没有确定最大耐受剂量。 69.0% 的患者发生治疗相关不良事件 (TRAE)； 3/4 级和严重 TRAE 的发生率分别为 31.0% 和 18.3%。 TRAE 导致 9.9% 的患者停药。没有出现与治疗相关的死亡。 ORR 为 5.6%（95% 置信区间 1.6-13.8），包括 1 例完全缓解和 3 例部分缓解，所有患者均进行剂量扩展且 PD-L1 TC ≥25%，且既往未接受过免疫治疗；其中三人的持续反应时间≥12 个月。总人口的中位总生存期为 8.6 个月。在所有队列中，可溶性 PD-L1 抑制几乎完全，表明目标参与。所有剂量扩展​​组中 CD4 Ki67 T 细胞均显着升高。治疗耐受性良好。然而，尽管靶点参与、没有药物间相互作用、也没有 durvalumab 药物中和抗体，但缓解率仍然很低。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741).In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity.A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts.Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.