Quemliclustat and chemotherapy with or without zimberelimab in metastatic pancreatic adenocarcinoma: a randomized phase 1 trial.

In a phase 1b trial (ARC-8), we evaluated safety and efficacy of quemliclustat combined with gemcitabine/nab-paclitaxel (G/nP) with or without zimberelimab (anti-programmed cell death protein 1 (PD-1)) in first-line metastatic pancreatic ductal adenocarcinoma (PDAC).

在一项1b期试验（ARC-8）中，我们评估了Quemliclustat联合吉西他滨/白蛋白结合型紫杉醇（G/nP）以及是否联合Zimberelimab（抗程序性细胞死亡蛋白1（PD-1））在一线转移性胰腺导管腺癌（PDAC）中的安全性和有效性。

During the dose-escalation phase, 22 patients were enrolled across five dose levels of quemliclustat (25 mg, 50 mg, 75 mg, 100 mg or 125 mg) with G/nP + zimberelimab.

在剂量递增阶段，共有22名患者参与，分在五个剂量水平的quemliclustat（25毫克、50毫克、75毫克、100毫克或125毫克）联合G/nP + zimberelimab治疗。

During the dose-expansion phase, 116 patients were enrolled, beginning with a single-arm, non-randomized cohort receiving quemliclustat 100 mg + G/nP + zimberelimab, followed by a randomized cohort in which patients were assigned in a 2:1 ratio to receive quemliclustat 100 mg + G/nP with or without zimberelimab.

在剂量扩展阶段，共有116名患者参与，首先是一个单臂、非随机的队列，接受quemliclustat 100毫克 + G/nP + zimberelimab治疗，随后是一个随机队列，患者以2:1的比例被分配接受quemliclustat 100毫克 + G/nP，有或没有zimberelimab。

The primary endpoint was safety and tolerability; secondary endpoints included assessments of clinical activity and survival. In all treatment arms, the safety profile was consistent with that of G/nP.

主要终点是安全性和耐受性；次要终点包括对临床活性和生存的评估。在所有治疗组中，安全性特征与G/nP一致。

Clinical response rates and survival outcomes were encouraging.

临床反应率和生存结果令人鼓舞。

NR4A family gene expression was upregulated by adenosine in vitro and by chemotherapy in human PDACs.

NR4A家族基因表达在体外通过腺苷上调，在人类胰腺导管腺癌（PDACs）中通过化疗上调。

High tumor NR4A expression was associated with improved overall survival(OS) in ARC-8 but not in two external cohorts from the PRINCE (G/nP + nivolumab (nivo)) or Morpheus-PDAC (G/nP) trials.

高肿瘤NR4A表达与ARC-8中的总生存（OS）改善相关，但在PRINCE（G/nP + nivolumab（nivo））或Morpheus-PDAC（G/nP）试验的两个外部队列中并未显示出相关性。

Spatial tissue analyses revealed a scarcity of activated T cells near regions with high NR4A1 expression, consistent with an immunosuppressed tumor microenvironment.

空间组织分析揭示，在高NR4A1表达区域附近，活化的T细胞数量较少，这与免疫抑制的肿瘤微环境相符。

In paired pretreatment/posttreatment biopsies, maximal downregulation of NR4A expression was associated with T cell activation and improved OS, pointing to a biological link between tumor adenosine and clinical benefit.

在配对的治疗前/后活检样本中，NR4A表达的最大下调与T细胞激活和总生存期（OS）的改善相关，这表明肿瘤腺苷与临床益处之间存在生物学联系。

ClinicalTrials.gov identifier: NCT04104672 .

临床试验注册号：NCT04104672 .