Phase 1 evaluation of ASP3082, a first-in-class selective protein degrader, in patients (pts) with KRAS G12D -mutant pancreatic ductal adenocarcinoma (PDAC): Pharmacokinetics (PK) and biomarker insights.

作者：W. Park, Anup Kumar Kasi, Jonathan W. Goldman, Meredith Pelster, Benjamin Herzberg, Anthony W. Tolcher, Alexander I. Spira, Antoine Hollebecque, H. Shoji, Yasutoshi Kuboki, Judy S. Wang, Jordan Berlin, Shilpa Kadam, H. Lee, Stanley C. Gill, Takeshi Saito, Joseph Carlton Poythress, Junko Toyoshima, Hisaki Fujii, Shigehisa Kitano · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.2_suppl.775 · 被引用次数：1 · 研究领域：HER2/EGFR in Cancer Research、Peptidase Inhibition and Analysis、Monoclonal and Polyclonal Antibodies Research

775 Background: KRAS G12D is a critical oncogenic driver and a high-priority therapeutic target in PDAC. ASP3082, a first-in-class KRAS G12D-selective protein degrader, showed antitumor activity in pts with PDAC in an ongoing Phase 1 study (NCT05382559). We report findings from exploratory analyses of this study. Methods: Adults with previously treated locally advanced unresectable/metastatic or treatment-naïve metastatic KRAS G12D -mutant PDAC were included. Pts received escalating doses (10–800mg) of ASP3082 IV once weekly (QW) in 21-day cycles. Evidence of efficacy emerged in doses ≥140mg and are presented here. Plasma concentration of ASP3082 was measured for pharmacokinetics. Pharmacodynamic analyses included KRAS G12D protein and phosphorylated ERK (pERK) measured by IHC in paired tumor biopsies; circulating tumor (ct) DNA KRAS G12D variant allele frequency (VAF) at baseline (BL) and on-treatment and serum CA19-9 and carcinoembryonic antigen (CEA) levels were assessed. Results: DCO was Feb 23, 2025. Samples from 124 pts with KRAS G12D -mutant PDAC (10–90mg=26; 140mg=5; 200mg=12; 300mg=30; 450mg=10; 600mg=31; 800mg=10) were included. BL demographics and clinical characteristics were similar across cohorts. ASP3082 showed a biphasic plasma concentration–time profile, with C max reached at end of infusion, then rapid distribution and slow elimination (t 1/2 ~40 hr). No accumulation occurred with QW dosing, and area under the curve (AUC) increased more than dose-proportiona...