Scholarlink

<p>Quemliclustat potently inhibits CD73, a key enzyme producing immunosuppressive adenosine. 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). 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. 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. 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. Clinical response rates and survival outcomes were encouraging. <i>NR4A</i> family gene expression was upregulated by adenosine in vitro and by chemotherapy in human PDACs. High tumor <i>NR4A</i> 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. Spatial tissue analyses revealed a scarcity of activated T cells near regions with high <i>NR4A1</i> expression, consistent with an immunosuppressed tumor microenvironment. In paired pretreatment/posttreatment biopsies, maximal downregulation of <i>NR4A</i> expression was associated with T cell activation and improved OS, pointing to a biological link between tumor adenosine and clinical benefit. ClinicalTrials.gov identifier: <a href="http://clinicaltrials.gov/study/NCT04104672">NCT04104672</a>.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月30日

查看全文
  • Zev A. Wainberg,
  • Gulam A. Manji,
  • Nathan Bahary,
  • Susanna V. Ulahannan,
  • Shubham Pant,
  • David R. Spigel,
  • Nataliya V. Uboha,
  • Paul E. Oberstein,
  • Anwaar Saeed,
  • Brandon Beagle,
  • Ji Yun Kim,
  • Ning Wang,
  • Ben Weeder,
  • Shravani Shitole,
  • Karim Mrouj,
  • Jennifer R. Scott,
  • Lisa G. Ensign,
  • Daniel M. DiRenzo,
  • Matthew J. Walters,
  • Wilson Wu,
  • Angelo Kaplan,
  • Soonweng Cho,
  • Omar Kabbarah,
  • Eileen M. O’Reilly

摘要

Quemliclustat potently inhibits CD73, a key enzyme producing immunosuppressive adenosine. 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). 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. 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. 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. Clinical response rates and survival outcomes were encouraging. NR4A family gene expression was upregulated by adenosine in vitro and by chemotherapy in human PDACs. 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. Spatial tissue analyses revealed a scarcity of activated T cells near regions with high NR4A1 expression, consistent with an immunosuppressed tumor microenvironment. 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. ClinicalTrials.gov identifier: NCT04104672.