Quemliclustat and chemotherapy with or without zimberelimab in metastatic pancreatic adenocarcinoma: a randomized phase 1 trial
Summary
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
Content
# Quemliclustat and chemotherapy with or without zimberelimab in metastatic pancreatic adenocarcinoma: a randomized phase 1 trial
*Published: 2026 Apr*
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 .
DOI: 10.1038/s41591-026-04283-z