Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits a multimodal mechanism of action based on antitumor activity in preclinical models of cancer, including pancreatic. The efficacy and safety of elraglusib with gemcitabine plus nab-paclitaxel (GnP) were assessed in patients with previously untreated mPDAC. In an open-label, international, multicenter, phase 2 study, patients were randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (OS) and 1-year survival rate. The prespecified modified intention-to-treat population included 155 patients on elraglusib/GnP and 78 on GnP. As of the data cutoff of 27 April 2025, elraglusib/GnP improved median OS by 2.9 months and decreased the risk of death by 38% versus GnP (median OS 10.1 months versus 7.2 months, respectively (hazard ratio 0.62; 95% confidence interval 0.46 to 0.84; P = 0.01)). The 1-year survival rates were 44.1% versus 22.3%, respectively. The safety profile of elraglusib/GnP was manageable. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with elraglusib/GnP versus GnP alone were neutropenia (52.3% versus 30.8%), anemia (25.2% versus 29.5%) and fatigue (16.8% versus 5.1%). Explorative correlative analyses demonstrated that baseline circulating immune-related factors (that is, CXCL2 and TRAIL ligands) were associated with improved survival in the elraglusib/GnP arm. Treatment was accompanied by increases in intratumoral cytotoxic immune cell populations. Together, these findings support the clinical activity of elraglusib/GnP as first-line treatment in mPDAC and provide a biological context for the observed survival benefit. Based on the results of this phase 2 trial, a phase 3 trial is being planned. ClinicalTrials.gov registration: NCT03678883.

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Journal
Nature Medicine
Published
2026-04-14
DOI
https://doi.org/10.1038/s41591-026-04327-4
Primary Topic
Pancreatic and Hepatic Oncology Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial

Ryan M. Carr, Anne Ploquin, Noelle K. LoConte, Devalingam Mahalingam et al.
Nature Medicine
Pancreatic and Hepatic Oncology Research
article

Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial

Ryan M. Carr, Anne Ploquin, Noelle K. LoConte, Devalingam Mahalingam, Rachna T. Shroff, T. Bekaii-Saab, Sandrine Hiret, Andrew L. Coveler, Francis J. Giles, Andrey Ugolkov, Andrew P. Mazar, Benedito A. Carneiro, Vaibhav Sahai, Gil Fine, Charles D. Lopez, Chris Seifarth, Mark Jaros, Andres Cervantes, Yan Ji, Ivor J. Percent, Taylor Weiskittel, Petr Kavan, Simon Pernot, Mary Mulcahy
article en

Abstract

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits a multimodal mechanism of action based on antitumor activity in preclinical models of cancer, including pancreatic. The efficacy and safety of elraglusib with gemcitabine plus nab-paclitaxel (GnP) were assessed in patients with previously untreated mPDAC. In an open-label, international, multicenter, phase 2 study, patients were randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (OS) and 1-year survival rate. The prespecified modified intention-to-treat population included 155 patients on elraglusib/GnP and 78 on GnP. As of the data cutoff of 27 April 2025, elraglusib/GnP improved median OS by 2.9 months and decreased the risk of death by 38% versus GnP (median OS 10.1 months versus 7.2 months, respectively (hazard ratio 0.62; 95% confidence interval 0.46 to 0.84; P = 0.01)). The 1-year survival rates were 44.1% versus 22.3%, respectively. The safety profile of elraglusib/GnP was manageable. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with elraglusib/GnP versus GnP alone were neutropenia (52.3% versus 30.8%), anemia (25.2% versus 29.5%) and fatigue (16.8% versus 5.1%). Explorative correlative analyses demonstrated that baseline circulating immune-related factors (that is, CXCL2 and TRAIL ligands) were associated with improved survival in the elraglusib/GnP arm. Treatment was accompanied by increases in intratumoral cytotoxic immune cell populations. Together, these findings support the clinical activity of elraglusib/GnP as first-line treatment in mPDAC and provide a biological context for the observed survival benefit. Based on the results of this phase 2 trial, a phase 3 trial is being planned. ClinicalTrials.gov registration: NCT03678883.

Nature Medicine
Northwestern University (US), University of Arizona (US), Universitat de València (ES), Oregon Health & Science University (US), Université de Lille (FR), Brown University (US), University of Michigan (US), Jewish General Hospital (CA), Fred Hutch Cancer Center (US), University of Wisconsin Carbone Cancer Center (US), Institut de Cancérologie de l'Ouest (FR), Florida Cancer Specialists & Research Institute (US), Metro-Minnesota Community Oncology Research Consortium (US), Mayo Clinic in Arizona (US), Mayo Clinic Hospital (US), Institut Bergonié (FR), Lifespan (US), Fate Therapeutics (United States) (US), INCLIVA Health Research Institute (ES), University of Arizona Cancer Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Excelsior College (US)
Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Gilead Sciences, Brown University, FibroGen, Boston Scientific Corporation, Regeneron Pharmaceuticals, Taiho Pharmaceutical, Exelixis, Novocure, Halozyme, BeiGene, XBiotech, NuCana, NGM Biopharmaceuticals, Actuate Therapeutics, Seagen, Natera, Eisai, Astellas Pharma, Servier, Ipsen, Genentech, Foundation Medicine
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Openalex Percentile: Top 24%
Pancreatic and Hepatic Oncology Research
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