A phase 2 study of STING agonist ADU-S100 combined with a CLDN18.2 bispecific antibody in patients with advanced pancreatic cancer.

749 Background: STING agonists can remodel the tumor immune microenvironment by inducing innate immunity and promoting stem-like CD8+ T-cell populations, which may synergize with T-cell-engaging therapies. Preclinical models of PDAC showed that a STING agonist enriched for stem-like TCF-1 + CD8 + T cells and significantly enhanced the efficacy of CLDN18.2 bispecific antibodies. Methods: This phase 2 trial enrolled pts with advanced CLDN18.2-positive PDAC. Pts received the STING agonist ADU-S100 (intratumoral injections 50µg-100µg either weekly) in combination with CLDN18.2 BsAb (intravenous injections at 6 mg/kg once every 3 weeks). The primary objective was ORR, Secondary objectives included DCR, PFS, TRAEs and changes in tumoral and peripheral CD8⁺ T-cell subsets (total CD8⁺, PD-1⁺CD8⁺, and TCF-1⁺CD8⁺ T cells). Results: As of the data cutoff, 15 pts were enrolled. TRAEs occurred in 93% of pts, with 27% experiencing grade ≥3 TRAEs. The most common TRAEs were decreased white blood cell count (40.1%, including 10.5% grade ≥3), anemia (38.7%, including 14.9% grade ≥3), decreased neutrophil count (35.2%, including 16.8% grade ≥3), decreased appetite (30.3%, including 2.2% grade ≥3), nausea (23.6%, including 1.5% grade ≥3), hypoalbuminemia (20.8%, all grade 1–2), and decreased platelet count (22.9%, including 5.1% grade ≥3). Treatment was discontinued in 3 pts (21.4%) due to disease progression. Among 14 response-evaluable pts, 7 achieved partial response (PR), 3 had stable disease (SD), and 4 had progressive disease (PD), yielding a confirmed ORR of 50% and a DCR of 71.4%. PFS data were not mature. Biomarker analyses revealed significant immune activation post-treatment. In tumor tissue, the density of total CD8⁺ T cells increased from a mean of 98.6 ± 30.4 to 220.3 ± 45.1 cells/mm² (p < 0.01), PD-1⁺CD8⁺ T cells increased from 15.2 ± 6.8 to 48.5 ± 12.3 cells/mm² (p < 0.01), and the stem-like TCF-1⁺CD8⁺ subset increased from 5.1 ± 2.5 to 18.7 ± 7.2 cells/mm² (p < 0.01). In peripheral blood, the frequency of total CD8⁺ T cells increased from 25.4% ± 8.2% to 38.9% ± 9.7% (p < 0.05), PD-1⁺CD8⁺ T cells from 5.3% ± 2.1% to 12.6% ± 4.3% (p < 0.01), and TCF-1⁺CD8⁺ T cells from 2.1% ± 1.0% to 6.8% ± 2.5% (p < 0.01). Responders (PR+SD) exhibited significantly higher post-treatment levels of all CD8⁺ T-cell subsets in both tumor and blood compared to non-responders (PD) (p < 0.05 for all comparisons). Conclusions: Combining the STING agonist ADU-S100 with a CLDN18.2 BsAb is feasible with a predictable safety profile. The regimen shows promising clinical activity and induces favorable immune changes in the tumor microenvironment of PDAC pts, supporting further development of this combination strategy.