Preliminary efficacy and biomarker analysis of CLDN18.2-targeted ADC combined with the NET inhibitor sivelestat in female patients with advanced CLDN18.2-positive pancreatic adenocarcinoma.

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