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

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

doi:10.1038/s41591-026-04327-4

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

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

Gil Fine, Mark Jaros, Andrew P. Mazar, Tanios S. Bekaii-Saab

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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

Original language	English (US)
Pages (from-to)	1794-1804
Number of pages	11
Journal	Nature Medicine
Volume	32
Issue number	5
DOIs	https://doi.org/10.1038/s41591-026-04327-4
State	Published - May 2026
Externally published	Yes

ASJC Scopus subject areas

General Medicine
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41591-026-04327-4

Cite this

Mahalingam, D., Shroff, R. T., Carneiro, B. A., Ji, Y., Coveler, A. L., Cervantes, A., Sahai, V., Ploquin, A., Hiret, S., LoConte, N. K., Percent, I. J., Lopez, C. D., Pernot, S., Kavan, P., Mulcahy, M., Carr, R., Giles, F. J., Seifarth, C., Ugolkov, A., ... Bekaii-Saab, T. S. (2026). Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial. Nature Medicine, 32(5), 1794-1804. https://doi.org/10.1038/s41591-026-04327-4

Mahalingam, D, Shroff, RT, Carneiro, BA, Ji, Y, Coveler, AL, Cervantes, A, Sahai, V, Ploquin, A, Hiret, S, LoConte, NK, Percent, IJ, Lopez, CD, Pernot, S, Kavan, P, Mulcahy, M, Carr, R, Giles, FJ, Seifarth, C, Ugolkov, A, Weiskittel, T, Fine, G, Jaros, M, Mazar, AP & Bekaii-Saab, TS 2026, 'Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial', Nature Medicine, vol. 32, no. 5, pp. 1794-1804. https://doi.org/10.1038/s41591-026-04327-4

@article{417f65c4081d4dd7b6d20589b765763d,

title = "Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial",

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",

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

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = may,

doi = "10.1038/s41591-026-04327-4",

language = "English (US)",

volume = "32",

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T1 - Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma

T2 - a randomized controlled phase 2 trial

AU - Mahalingam, Devalingam

AU - Shroff, Rachna T.

AU - Carneiro, Benedito A.

AU - Ji, Yan

AU - Coveler, Andrew L.

AU - Cervantes, Andres

AU - Sahai, Vaibhav

AU - Ploquin, Anne

AU - Hiret, Sandrine

AU - LoConte, Noelle K.

AU - Percent, Ivor J.

AU - Lopez, Charles D.

AU - Pernot, Simon

AU - Kavan, Petr

AU - Mulcahy, Mary

AU - Carr, Ryan

AU - Giles, Francis J.

AU - Seifarth, Chris

AU - Ugolkov, Andrey

AU - Weiskittel, Taylor

AU - Fine, Gil

AU - Jaros, Mark

AU - Mazar, Andrew P.

AU - Bekaii-Saab, Tanios S.

PY - 2026/5

Y1 - 2026/5

N2 - 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

AB - 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

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EP - 1804

JO - Nature Medicine

JF - Nature Medicine

IS - 5

ER -

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

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