度伐利尤单抗联合替西木单抗治疗复发性/转移性头颈部鳞状细胞癌的安全性和临床活性：一项多中心 I 期研究。

Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study.

机构信息

Head and Neck Medical Oncology Program, University of California, San Francisco.

Clinical Research, South Texas Accelerated Research Therapeutics (START), San Antonio.

出版信息

ESMO Open. 2024 Aug;9(8):103646. doi: 10.1016/j.esmoop.2024.103646. Epub 2024 Jul 23.

DOI:10.1016/j.esmoop.2024.103646

PMID:39043009

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11325272/

Abstract

BACKGROUND

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).

METHODS

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.

RESULTS

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.

CONCLUSIONS

Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.

摘要

背景

程序性死亡蛋白 1（PD-1）抑制剂在复发性/转移性头颈部鳞状细胞癌（R/M HNSCC）中比化疗能延长生存期，这些癌症通常表达细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）和程序性死亡配体 1（PD-L1），为联合 PD-（L）1 和 CTLA-4 阻断提供了依据。我们报告了一项 I 期、开放标签的 PD-L1 抑制剂 durvalumab 联合 CTLA-4 抑制剂 tremelimumab 的研究（NCT02262741）。

方法

在剂量探索中，两组先前接受过治疗的患者接受 durvalumab 10 mg/kg 联合 tremelimumab 3 mg/kg，或 durvalumab 20 mg/kg 联合 tremelimumab 1 mg/kg，持续 12 个月。剂量扩展包括三组先前未经治疗的 R/M HNSCC 患者，其基线 PD-L1 肿瘤细胞（TC）表达≥25%和<25%，以及一组任何 PD-L1 水平的免疫治疗预处理患者。所有患者均接受 durvalumab 20 mg/kg 联合 tremelimumab 1 mg/kg，然后 durvalumab 10 mg/kg，持续 12 个月。主要终点是安全性。次要终点是按 RECIST 版本 1.1 评估的客观缓解率（ORR）、药代动力学、药效学和免疫原性。

结果

共有 71 名患者接受了治疗。durvalumab 的中位暴露时间为 13.6 周，tremelimumab 为 13.1 周。在剂量探索中，未发生剂量限制毒性。未确定最大耐受剂量。治疗相关不良事件（TRAEs）发生在 69.0%的患者中；3/4 级和严重 TRAEs 分别为 31.0%和 18.3%。TRAEs 导致 9.9%的患者停药。无治疗相关死亡。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，所有患者均在剂量扩展组中，PD-L1 TC≥25%且无先前免疫治疗暴露；3 例持续缓解≥12 个月。总人群的中位总生存期为 8.6 个月。所有队列的可溶性 PD-L1 抑制几乎完全，表明靶标结合。所有剂量扩展队列的 CD4+Ki67+T 细胞均显著升高。