A phase II study of FOLFIRINOX (FFX) combined with the glycogen synthase kinase-3beta (GSK-3β) inhibitor elraglusib (ELRA) and the transforming growth factor beta (TGFβ) inhibitor losartan (LOS) in patients with untreated metastatic pancreatic ductal

4212 Background: Concurrent inhibition of GSK-3β and TGF-β signaling pathways aims to target epithelial-mesenchymal transition (EMT) plasticity, metabolic reprogramming, desmoplasia and immune escape mechanisms that underlie therapeutic resistance in mPDAC Methods: In this multi-institutional, open-label, four-arm (non-comparator) phase II trial conducted across three academic centers in the United States, 49 patients with newly diagnosed, treatment naive mPDAC were randomized to Arm 1: FFX alone (biomarker control, n=4) or Arm 2: FFX plus LOS (50 mg daily); Arm 3: FFX plus ELRA (9.3 mg/kg IV twice weekly); Arm 4: FFX plus LOS plus ELRA (n=15/arm). After 12 cycles of FFX without progression, patients transitioned to maintenance 5-FU (plus ELRA/LOS, based on the arm) and resumed full therapy at progression; treatment withdrawal required progression on full therapy or treatment-limiting toxicity. The primary endpoint was progression-free survival (PFS). Results: Between September 19, 2022, and January 2, 2025, 49 patients were enrolled (median age 65 years; 51% female; 74% White). At the data cutoff (July 6, 2025), 14 (28.6%) patients remained alive with a median follow-up of 9 months. Median PFS was 5.1 months (95% CI 1.1–NR) in Arm 1, 5.9 months (95% CI 1.6–9.9) in Arm 2, 6.0 months (95% CI 1.8–9.8) in Arm 3, and 6.5 months (95% CI 3.8–8.5) in Arm 4. 9-month PFS could not be calculated in arm 1, 29.3% (95% CI 9.2-53.3) in Arm 2, 37.3% (95% CI 13.6 – 61.5%) in Arm 3, and 21.7% (95% CI 5.3 –45.1) in Arm 4. Median overall survival (OS) was 7.7 months (95% CI 1.1–NR), 8.2 months (95% CI 3.3–14.5), 9.8 months (95% CI 4.3–NR), and 9.8 months (95% CI 5.6–15.6), respectively in each arm. Objective response rate 24.5% (12/49);stable disease 44.9% (22/49). 14/49 (28.5%) patients received maintenance therapy, with a median duration of 2.4 months. Treatment was generally well tolerated, grade ≥3 treatment-related adverse events occurred in 34.7% of patients; one treatment-related death due to sepsis occurred in Arm 3. Notably, a subset of patients in Arms 3 and 4 demonstrated deep and sustained clinical responses; Correlative biomarker analyses are ongoing to identify molecular and immune features associated with these long term responders. Conclusions: Although clinical outcomes with the novel combinations did not exceed historical standards of care, this non-comparator phase II study demonstrates the feasibility and tolerability of combinatorial pathway inhibition in mPDAC. This study enables ongoing correlative analyses of EMT plasticity, stromal remodeling, and immune escape in mPDAC and establishes a robust platform to define determinants of resistance and durable response. Clinical trial information: NCT05077800 .