748 Background: The dense desmoplastic stroma of PDAC, driven by cancer-associated fibroblasts (CAFs), is a major barrier to effective therapy. Preclinical data (Zhou et al., Gut) demonstrated that targeting CD64 + CAFs with vilanterol, a β2-adrenergic receptor agonist, reduces desmoplasia and augments the efficacy of CLDN18.2-targeting bispecific antibodies (BsAbs) by inhibiting stromal immunosuppression. This phase 2 study evaluates the safety and preliminary efficacy of this novel combination in advanced PDAC. Methods: Eligible patients (pts) with advanced CLDN18.2-positive PDAC who failed prior therapies were enrolled. Vilanterol (25mcg/umeclinidium 62.5mcg) was administered via inhalation QOD. A CLDN18.2 BsAb was given intravenously at a dose of 6 mg/kg Q3W. The primary objective was ORR. Secondary objectives included DCR, PFS, TRAEs, the α-SMA + stromal density and CD8 + T-cell infiltration level. Results: As of the data cutoff, 14 pts were enrolled. TRAEs occurred in 96% of pts, with 30% experiencing grade ≥3 TRAEs. The most common TEAEs were a decrease in white blood cell count (43.2%, including 12.4% with grade 3 and higher TEAEs), anemia (42.5%, including 16.4% with grade 3 and higher TEAEs), a decrease in neutrophil count (38.4%, including 18.4% with grade 3 and higher TEAEs), decreased appetite (32.5%, including 2.6% with grade 3 and higher TEAEs), nausea (25.3%, including 1.7% with grade 3 and higher TEAEs), hypoalbuminemia (22.4%, all grade 1–2) and a decrease in platelet count (24.5%, including 5.8% with grade 3 and higher TEAEs). Treatment was discontinued in 3 pts (21.4%) due to disease progression. Among 12 response-evaluable pts, 6 had partial responses (PRs), 3 had stable disease (SD) and 3 had progressed disease (PD). The confirmed ORRs were 50% and the DCR was 75.0%. PFS data were not mature. Matched pre- and post-treatment biopsies showed a significant reduction in α-SMA⁺ stromal density (from mean 42.5% ± 8.3% to 23.7% ± 6.5%; p < 0.01) and a marked increase in CD8⁺ T-cell infiltration (from mean 105.4 ± 35.2 cells/mm² to 258.6 ± 42.7 cells/mm²; p < 0.001) following treatment. Multiplexed IHC further revealed that responders (PR+SD) exhibited significantly lower post-treatment α-SMA⁺ stromal density (20.4% ± 5.1% vs. 38.6% ± 7.2%; p < 0.01) and higher CD8⁺ T-cell infiltration (291.5 ± 38.4 cells/mm² vs. 132.7 ± 28.6 cells/mm²; p < 0.001) compared to non-responders (PD). Conclusions: The combination of vilanterol and a CLDN18.2 BsAb demonstrates a manageable safety profile and encouraging antitumor activity in heavily pre-treated pts with CLDN18.2-positive PDAC. Stromal modulation represents a viable strategy to enhance the efficacy of T-cell-engaging therapies.
Tianxing Zhou (Sat,) studied this question.