Results from the randomized phase 2 study (1801 Part 3B) of elraglusib plus gemcitabine/nab-paclitaxel (GnP) versus GnP in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

Abstract

653 Background: Elraglusib (9-ING-41), a novel small molecule inhibitor of GSK-3ß, has a multimodal mechanism of action that enhances chemotherapy cytotoxicity and regulates anti-tumor immune cell response. Elraglusib was evaluated in a randomized, open-label, phase 2 study (NCT03678883) comparing elraglusib/GnP vs GnP in previously untreated mPDAC. Methods: Pts were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP. Primary endpoint was mOS, with 1-yr OS rate estimates summarizing clinical benefit throughout the study. Secondary endpoints were ORR, mPFS, and TEAEs/TRAEs. Pre-dose cytokines, mutational analysis, and immunophenotyping were correlated with outcomes. An oral presentation at ASCO 2025 discussed preliminary data. Results: As of 27 April 2025, the primary analysis set included 155 pts in the elraglusib/GnP arm and 78 pts in the GnP arm, with 52.8% males and 57.5% ECOG PS 1. The 1-yr OS rate was 44.1% with elraglusib/GnP vs 22.3% with GnP; the mOS was 10.1 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.62; p=0.01) with approximately 79% events recorded (25.8% of pts on elraglusib/GnP and 10.3% on GnP were censored with the majority at >12 mo OS). Improved OS with elraglusib/GnP was consistent across all randomized pts and subgroups regardless of liver metastases, ECOG status, or baseline CA 19-9 levels. Most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment (66.5% pts vs 0 with GnP). Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 52.3% (vs 30.8%) and anemia 25.2% (vs 29.5%). No differences in sepsis/febrile neutropenia rates were between arms. RAS , TP53 and CDKN2A co-mutations were associated with worse OS in the elraglusib/GnP arm only (p<0.05). Elevation in pre-dose cytokines including CXCL2 correlated with improved OS in the elraglusib/GnP arm. Additionally, increased CD8+ T cells, granzyme B, and NK cells and reduced MDSCs were observed in elraglusib-treated tumors. Conclusions: A significant benefit for 1-yr OS and mOS and a favorable trend for ORR were observed with the addition of elraglusib to GnP. The mOS was lower in the GnP arm vs historical studies, likely due to early deaths in the first 2 months, but aligns with mOS estimates in the real-world analysis with broad heterogeneous population. Our study included 19.7% pts with albumin <3.0 g/dL and >25% with CA 19.9 levels > 8,000 U/mL. Immune correlates support elraglusib’s immune-modulatory role. Final efficacy data cut-off in Dec 2025 and correlative studies will be presented. Clinical trial information: NCT03678883 . Outcome Elraglusib/GnPN=155 GnPN=78 Primary endpoint: mOS (mo)HR=0.62; log-rank p=0.01 10.1 7.2 Events, n (%) 115 (74.2) 70 (89.7) Primary endpoint: 1-yr OS (%) 44.1 22.3 18-month OS (%) 20.5 4.4 24-month OS (%) 13.2 0 mPFS (mo)HR=0.9; p=NS 5.6 5.1 Events, n (%) 136 (87.7) 75 (96.2) ORR, n (%) 44 (28.4) 17 (21.8)