LoConte, Noelle K.

4213 Background: Elraglusib (9-ING-41), a glycogen synthase kinase-3β (GSK-3β) inhibitor, has multimodal antitumor activity. In the international, open-label, randomized phase 2 1801 Part 3B study, elraglusib plus gemcitabine/nab-paclitaxel (GnP) was evaluated in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC), with patients randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (mOS) and 1-year survival. The GnP control arm demonstrated shorter mOS than contemporary randomized trials (7.2 months vs 9.2 months in NAPOLI-3 and 9.7 months in PASS-01), driven by higher early mortality (0–2 months: 23.1% vs 10.1% in NAPOLI-3). Given balanced randomization, similar early mortality was inferred in the elraglusib/GnP arm, prompting post-hoc analyses to contextualize efficacy and identify factors associated with early death. Methods: Efficacy and safety were summarized descriptively. Time-to-event endpoints were analyzed using Kaplan–Meier estimates, log-rank testing, and Cox proportional hazards models. Response rates were compared using the Cochran–Mantel–Haenszel test. Post-hoc subgroup, sensitivity, and machine-learning–based multivariate analyses explored clinical, demographic, and biomarker correlates of survival and early mortality. Results: In the full randomized population (elraglusib/GnP n=155; GnP n=78), elraglusib/GnP improved mOS by 2.9 months versus GnP (10.1 vs 7.2 months; HR 0.62; 95% CI 0.46–0.84; p=0.01), with 1-year survival rates of 44.1% versus 22.3%. Among patients receiving ≥1 full treatment cycle, mOS was 12.5 months with elraglusib/GnP and 8.5 months with GnP, comparable to contemporary registrational trials. Across multiple post-hoc sensitivity analyses—including evaluable patients, those matched to NAPOLI-3 baseline tumor burden, patients treated in the EU (early mortality 4%), and those achieving ≥20% CA19-9 decline within the first 1–2 cycles—elraglusib/GnP consistently demonstrated a ≥4-month OS advantage. Early death was associated with low baseline albumin (<3 g/dL), high CA19-9 (>800 U/mL), high tumor burden, and KRAS, TP53, and CDKN2A co-mutations. Conclusions: The elevated early mortality in the GnP control arm reflects enrollment of a heterogeneous, real-world mPDAC population with less restrictive eligibility than recent registrational trials. Post-hoc analyses identify key clinical and molecular drivers of early death and confirm a consistent survival benefit with elraglusib/GnP. These hypothesis-generating findings directly inform eligibility criteria, stratification, and endpoint assumptions for the planned phase 3 trial. Clinical trial information: NCT03678883 .

761 Background: Glycogen Synthase Kinase-3β (GSK-3β) is a known therapeutic target in cancer including pancreatic adenocarcinoma (PDAC). The combination of elraglusib (9-ING-41), a novel GSK-3 inhibitor, and gemcitabine/nab-paclitaxel (GnP) is being evaluated as first-line therapy for patients with metastatic PDAC (mPDAC). We previously reported topline results indicating that the 1801 Part 3B phase 2 trial (NCT03678883) met its primary endpoint, showing a clinically meaningful survival benefit in patients treated with elraglusib/GnP compared to GnP alone. Here, we examined whether gene mutations correlated with clinical outcomes in mPDAC patients enrolled in this randomized phase 2 trial. Methods: For mutational analysis, archival tumor and/or plasma samples were obtained from 53 (GnP group) and 117 (elraglusib/GnP group) patients with previously untreated mPDAC. Cell-free DNA and/or tumor-extracted DNA were analyzed using the next generation sequencing. The comparison of the response rates was performed with the use of Chi-square tests. Kaplan-Meier survival curves were compared by log-rank (Mantel-Cox) tests. Results: Mutational analysis identified frequently mutated genes (detectable in ≥25% of patients): KRAS (141/170, 83%), TP53 (121/170, 71%), and CDKN2A (56/170, 33%). Mutations in KRAS, TP53, or CDKN2A genes did not correlate with objective response rate. Based on 81% of the recorded death events in the elraglusib/GnP group and 91% in the GnP group (topline data April, 2025), KRAS and TP53 gene mutations were associated with worse overall survival (OS) in patients treated with elraglusib/GnP (p<0.05) but not in GnP-treated patients. The rate of triple (KRAS+TP53+CDKN2A) mutations was significantly higher in the patients with OS<2 months as compared to the patients with OS>2 months in the elraglusib/GnP group (p<0.05) but not in the GnP group. Conclusions: Our preliminary results identified KRAS and TP53 gene mutations as potential predictive biomarkers of clinical outcome in elraglusib/GnP-treated mPDAC patients. Updated OS data and mutational analysis will be included in the final presentation. Clinical trial information: NCT03678883 .

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)

4006 Background: Elraglusib (9-ING-41) is a first-in-class inhibitor of GSK-3ß, which may mediate drug resistance, EMT, and damaged DNA and tumor immune response in advanced cancer. In pancreatic cancer models in mice, elraglusib combined with chemotherapy enhanced anti-tumor effects and survival. In a single-arm clinical study, elraglusib/GnP showed antitumor activity and prolonged survival in pts with mPDAC. Methods: Pts with previously untreated mPDAC were randomized 2:1 to GnP plus elraglusib 9.3 mg/kg IV once weekly or GnP in an open-label phase 2 study. The primary endpoint was 1-yr OS in the primary analysis set. Upon study completion, mOS will be the primary endpoint once survival distributions are compared after the 12-month follow-up using log-rank analysis. Secondary endpoints included DCR, ORR, mPFS, and TEAEs/TRAEs. The planned sample size was 207 evaluable pts (130 for elraglusib/GnP and 77 for GnP), assuming 1-yr OS of 55% with elraglusib/GnP and 35% with GnP to achieve 80% power with a chi-square test at a 2-sided 5% α. For OS, nonparametric log-rank test was used with statistical significance at p-value < 0.048. Cytokine/chemokine correlative biomarker assays were performed. The study completed enrollment in February 2024. Results: As of November 15, 2024 (preliminary data cut-off date), 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. Median (range) CA 19-9 levels were 1568 U/mL (1 to 381,904 U/mL) in the elraglusib/GnP arm and 1590 U/mL (2 to 501,000 IU/mL) in the GnP arm. The 1-yr OS rate was 43.6% with elraglusib/GnP vs 22.5% with GnP (z-test p = 0.002); the mOS was 9.3 mo with elraglusib/GnP vs 7.2 mo with GnP (HR, 0.63; log rank p = 0.016; see Table). 38.1% of pts on elraglusib/GnP and 19.2% on GnP are censored, with the majority at > 10 months OS. Several biomarkers appear to be predictive for OS including IFNβ and PD-L1. The most common TRAE with elraglusib/GnP was grade 1-2 transient visual impairment in > 60% of patients (vs 9% with GnP). Grade ≥3 TEAEs occurred in 89.7% of pts on elraglusib/GnP and 80.8% on GnP. Most common grade ≥3 TEAEs with elraglusib/GnP (vs GnP) were neutropenia 51.6% (vs 29.5%), anemia 24.5% (vs 29.5%), and fatigue 16.1% (vs 5.1%). Conclusions: The preliminary results showed a statistically significant benefit for 1-yr OS and mOS and favorable trends for ORR and DCR with elraglusib/GnP over GnP, with manageable safety profile. The mOS for GnP is lower relative to MPACT and NAPOLI-3 but comparable to recent real-world meta-analyses, explained by advanced disease burden and higher mortality rate in the first 4 months in our study. Topline analysis (April 2025) and correlative biomarker analysis predictive for OS will be presented. Clinical trial information: NCT03678883 . Preliminary efficacy results. Elraglusib/GnPn=155 GnPn=78 1-year OS, %z-test p=0.002 43.6 22.5 mOS, moHR=0.63; log-rank p=0.016 9.3 7.2 Events, n (%) 96 (61.9) 63 (80.8) mPFS, moHR=0.91; p=NS 5.6 4.9 Events, n (%) 128 (82.6) 70 (89.7) DCR, % 42.6 33.3 ORR, n (%) 43 (27.7) 16 (20.5)

Ampullary cancers refer to tumors originating from the ampulla of Vater (the ampulla, the intraduodenal portion of the bile duct, and the intraduodenal portion of the pancreatic duct), while periampullary cancers may arise from locations encompassing the head of the pancreas, distal bile duct, duodenum, or ampulla of Vater. Ampullary cancers are rare gastrointestinal malignancies, and prognosis varies greatly based on factors such as patient age, TNM classification, differentiation grade, and treatment modality received. Systemic therapy is used in all stages of ampullary cancer, including neoadjuvant therapy, adjuvant therapy, and first-line or subsequent-line therapy for locally advanced, metastatic, and recurrent disease. Radiation therapy may be used in localized ampullary cancer, sometimes in combination with chemotherapy, but there is no high-level evidence to support its utility. Select tumors may be treated surgically. This article describes NCCN recommendations regarding management of ampullary adenocarcinoma.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.