Smith, Sheri

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 .

Abstract Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.