Elraglusib Plus Chemo Enhances Survival Vs Chemo Alone in Metastatic PDAC

A survival benefit was noted when elraglusib was added to chemotherapy for patients with metastatic PDAC.

Results from a phase 2 trial (NCT03678883) highlighted that elraglusib plus gemcitabine/nab-paclitaxel had superior overall survival (OS) vs gemcitabine/nab-paclitaxel alone for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), according to a presentation from the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

In the open-label randomized phase 2 portion of the 1801 trial (NCT03678883) of patients with previously untreated disease, there was a 37% reduced risk of death in patients who received elraglusib (HR, 0.63; 95% CI; log-rank P = .01) in addition to chemotherapy, with manageable increases in toxicity including high-grade neutropenia and low-grade visual disturbances.

“Our study met its primary end point; elraglusib in combination with gemcitabine/nab-paclitaxel improved the median OS and reduced the risk of death by 37% compared with gemcitabine/nab-paclitaxel alone. We saw a near doubling of the 12-month OS rate at 44.1% vs 22.3%,” said Devalingam Mahalingam, MD, PhD, professor at the Feinberg School of Medicine in Chicago, Illinois, in his presentation.

Elraglusib (9-ING-41) is a first-in-class inhibitor of GSK-3ß, a cellular regulator that helps maintain balance in glucose metabolism, insulin signaling, and Wnt/ß-catenin activity, and is used by cancer cells for survival, growth, and immune evasion. Inhibiting GSK-3ß has been shown to reduce cancer cell proliferation and increase in T and NK cell activation in tumors.

There were 2 prior parts to this study. First, in an international, open-label, multicenter, nonrandomized phase 1 trial, elraglusib was given as monotherapy and in combination with chemotherapy in patients with advanced solid or hematologic malignancies, which determined a recommended phase 2 dose of 15 mg/kg twice weekly as a single agent.2 In a phase 2 single-arm study as first-line therapy for 42 patients with mPDAC, the dose in combination with gemcitabine/nab-paclitaxel was adjusted to 9.3 mg/kg twice weekly due to high incidence of grade 3 neutropenia and fatigue.3

Part 3B of the trial began with a 1:1:1 randomization of patients with untreated mPDAC to receive standard chemotherapy plus either elraglusib weekly, twice-weekly, or chemotherapy alone.1 Gemcitabine was given at 1000 mg/m2 and nab-paclitaxel was given at 125 mg/m2 on days 1, 8, and 15 of each 28-day cycle. The design was adjusted to a 2:1 randomization to weekly elraglusib after it was determined that the weekly dose was equivalent in efficacy to twice weekly and was easier for patient adherence.

In addition to the primary end points of median OS and 1-year OS during the trial run-in, secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to treatment failure (TTF), and disease control rate (DCR). The primary analysis population was a modified intent-to-treat (mITT) population including all patients who were randomly assigned and received at least 1 dose of treatment. A total of 287 patients were enrolled at 64 sites in 6 countries. Fifteen patients withdrew consent in the gemcitabine/nab-paclitaxel alone arm vs 5 in the elraglusib arm, which Mahalingam acknowledge could be a limitation of the open-label design.

The data cutoff for analysis was March 27, 2025. In the elraglusib arm, there were 155 patients with a median age of 65 years and in the chemotherapy alone arm there were 78 patients with a median age of 68 years. Approximately 57% of patients in both arms had an ECOG performance status of 1. The most common site of metastasis was the liver.

The median OS was 10.1 months in the experimental arm vs 7.2 months with chemotherapy alone. In addition to the near-doubling of the 12-month OS rate, the 18-month OS rate was 19.7% vs 4.4%, and the 24-month rate was 13.8% vs 0%, respectively.

“You will note this rapid decline in the first 2 months of the study in both arms, reflecting the aggressive nature of metastatic pancreatic cancer, but then you see that the curves start to diverge early and remain separated with reduced event rates in the elraglusib cohort, pointing to the survival benefit,” said Mahalingam. In discussion following his presentation, Mahalingam said the early decline of these patients could be attributed to poor biology in a subset of patients as well as this trial allowing a broader patient population which did not have cutoffs based on low albumin level or especially high CA 19-9 levels that have been excluded from some other trials.

Looking at subgroups such as baseline liver metastases, baseline ECOG performance status, baseline CA 19-9, all favored elraglusib, though some were too small to be significant.

The median PFS was 5.6 months for elraglusib vs 5.1 months with chemotherapy alone (HR, 0.90), and the TTF was 5.1 months vs 3.4 months, respectively (HR, 0.79), both lacking statistical significance. Approximately 50% of patients in both arms received additional lines of therapy, generally other combination chemotherapies.

The ORR was 29.0% with elraglusib including 1 complete response and several other deep partial responses, and some patients were sent for surgical resection following therapy, compared with an ORR of 21.8% with chemotherapy alone. The DCR was 61.3% vs 56.4%, respectively, and the median DOR was 5.5 months vs 4.0 months, respectively. Seven patients remained on treatment in the experimental cohort.

In terms of safety, nearly all patients had at least 1 treatment-emergent adverse event (TEAE) of any grade. The rate of serious TEAEs was comparable with 55.5% in the elraglusib arm vs 56.4% in the chemotherapy alone arm, whereas the rates of TEAEs leading to stoppage of a study drug were 27.1% vs 25.6%, respectively. The rate of TEAEs leading to death was 12.3% vs 16.7%, but treatment-related TEAEs leading to death were only 0.05% and 0.02%, respectively.

Visual impairment was reported in 67.7% of the patients receiving elraglusib compared with only 9.0% in the chemotherapy alone arm, but only 1 (0.6%) AE was grade 3 or higher. “These visual impairments were usually described as color and light perception changes that were usually mild and transient and often reversible within the first 12 hours of getting the infusion,” said Mahalingam. Additionally, fatigue was reported at a higher rate of 62.6% any-grade and 16.8% grade 3 or higher compared with 50.0% and 5.1%, respectively, in the chemotherapy arm.

Neutropenia was also more common with elraglusib, at 61.3% any-grade and 52.2% grade 3 or higher compared with 41.0% and 30.8%, respectively, in the other arm. Despite this, rates of febrile neutropenia and sepsis did not differ between the arms.

Patients had cytokine analyses done at baseline and after treatment, revealing that in patients with higher levels of CXCL2, there was a significant difference in probability of survival in the elraglusib arm (P = .001) but not in the comparator arm (P = .42), suggesting this is a predictive biomarker for benefit. Additionally, the percentage of CD8+ and granzyme B+ cells was significantly increased in patients treated with elraglusib, which supports its effect on the tumor microenvironment.

“Given where we are right now, we are hoping that this drug would allow some hope for progress in metastatic pancreatic cancer,” Mahalingam concluded.

References

1. Mahalingam D, Shroff R, Carneiro BA, et al. Preliminary results from the randomized phase 2 study (1801 part 3B) of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) versus GnP alone in patients (pts) with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol. 2025;43(suppl 16):4006. doi:10.1200/JCO.2025.43.16_suppl.4006
2. Carneiro BA, Cavalcante L, Mahalingam D, et al. Phase I study of Elraglusib (9-ING-41), a glycogen synthase kinase-3β inhibitor, as monotherapy or combined with chemotherapy inpatients with advanced malignancies. Clin Cancer Res. 2024;30(3):522-531. doi:10.1158/1078-0432.CCR-23-1916
3. Mahalingam D, Saeed A, Powell SF, et al. Phase 2 study of elraglusib (9-ING-41), a glycogen synthase kinase-3b inhibitor, in combination with gemcitabine plus nab-paclitaxel (GnP) in patients with previously untreated advanced pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2023;41(suppl 16):e16289. doi:10.1200/JCO.2023.41.16_suppl.e16289