718 Background: Estrogen-driven neutrophil extracellular trap (NET) formation has been identified as a key mechanism of resistance to CLDN18.2-targeted antibody-drug conjugates (ADCs) in female hosts according to our ongoing research. Preclinical data demonstrated that Sivelestat, a neutrophil elastase inhibitor, disrupts NETs and restores ADC efficacy. This ongoing phase II trial evaluates the novel combination of CLDN18.2 ADC and Sivelestat in this biomarker-selected population. Methods: Female patients (pts) with advanced CLDN18.2-positive (IHC ≥2+ in ≥40% tumor cells) pancreatic adenocarcinoma after ≥1 prior line of therapy were enrolled. Pts received CLDN18.2-ADC (6 mg/kg IV Q3W) plus Sivelestat (0.2 mg/kg/h via continuous IV infusion on Days 1-5 of each cycle). The primary endpoint was ORR. Secondary endpoints included DCR, PFS, TRAE and correlative biomarker analysis. Pre- and on-treatment plasma samples were collected to quantify NET markers (MPO-DNA complexes, Citrullinated Histone H3 Cit-H3) and IL-8 levels by ELISA. Results: As of the data cutoff, 8 patients were enrolled and evaluable. Median age was 64 years. Treatment-related adverse events (TRAEs) occurred in all pts (100%), mostly Grade 1-2. The most common TRAEs were nausea (55.0%), fatigue (50.0%), and neutropenia (30.0%). Grade ≥3 TRAEs occurred in 1 pts (12.5%), primarily neutropenia (n=1) and thrombocytopenia (n=1). No interstitial lung disease or treatment-related deaths were reported. The confirmed ORR was 37.5% (3/8), including 3 partial response (PR). The DCR was 75% (6/8). PFS are immature. Responders (PR+CR) exhibited a significantly greater reduction in plasma NET markers from baseline compared to non-responders (SD+PD) (MPO-DNA: -68.4% vs -12.5%, p<0.01; Cit-H3: -59.1% vs -8.7%, p<0.01). A concomitant decrease in IL-8 levels was also observed in responders (-52.3% vs -10.8%, p<0.05). Paired pre- and post-treatment plasma samples were analyzed for NET markers. Baseline levels of MPO-DNA complexes were 145.6 ± 28.4 U/mL, which decreased to 58.2 ± 16.7 U/mL after treatment (p<0.01). Similarly, Citrullinated Histone H3 (Cit-H3) levels decreased from 32.5 ± 6.8 ng/mL to 14.3 ± 4.2 ng/mL (p < 0.01). IL-8 levels also declined from 48.7 ± 10.2 pg/mL to 26.4 ± 7.5 pg/mL (p < 0.05). Conclusions: The combination of CLDN18.2-ADC and Sivelestat demonstrates a manageable safety profile and encouraging antitumor activity in heavily pretreated female patients with CLDN18.2 + advanced pancreatic cancer. The significant correlation between reduction in plasma NET burden and clinical response provides compelling translational evidence for the mechanism of action and supports the role of NETs as a mediator of sex-specific ADC resistance. These findings warrant further validation in randomized controlled trials.
Yan et al. (Sat,) studied this question.