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.
Tianxing Zhou (Sat,) studied this question.