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Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial
Devalingam Mahalingam1, Rachna T Shroff2, Benedito A Carneiro3
1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA. Mahalingam@northwestern.edu.
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.
Insights
Elraglusib combined with gemcitabine plus nab-paclitaxel significantly improved overall survival for metastatic pancreatic cancer patients. This combination therapy offers a promising new treatment option for advanced pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Clinical Pharmacology
- Immunotherapy
Background:
- Metastatic pancreatic ductal adenocarcinoma (mPDAC) has limited therapeutic advances and high mortality.
- Elraglusib (9-ING-41), a GSK-3β inhibitor, shows preclinical antitumor activity in pancreatic cancer.
- There is a need for novel first-line treatments for mPDAC.
Purpose of the Study:
- To assess the efficacy and safety of elraglusib combined with gemcitabine plus nab-paclitaxel (GnP) in previously untreated mPDAC patients.
- To evaluate overall survival (OS) and 1-year survival rates as primary endpoints.
- To explore potential biomarkers and immune correlates of response.
Main Methods:
- A phase 2, open-label, international, multicenter, randomized study.
- Patients were assigned 2:1 to weekly elraglusib/GnP or GnP alone.
- 155 patients received elraglusib/GnP, and 78 received GnP alone.
Main Results:
- Elraglusib/GnP demonstrated a median OS of 10.1 months vs. 7.2 months for GnP alone (HR 0.62, P=0.01), a 2.9-month improvement.
- 1-year survival rates were 44.1% for elraglusib/GnP versus 22.3% for GnP.
- The safety profile was manageable, with neutropenia, anemia, and fatigue as common grade ≥3 TEAEs.
Conclusions:
- Elraglusib/GnP shows significant clinical activity and improved survival in first-line mPDAC.
- Correlative analyses suggest immune-related factors (CXCL2, TRAIL) and increased intratumoral cytotoxic cells correlate with benefit.
- A phase 3 trial is planned based on these promising results.
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