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

Abstract

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-proportionally with escalating doses. KRAS G12D protein degradation (median 88%, IQR: 71.0–97.5%) in paired tumor biopsies post-treatment vs BL was observed at 600mg plus pERK suppression (median 46.5%, IQR: 38.9–56.0%), indicating RAS–MAPK pathway inhibition. Based on clinical and pharmacology data, ASP3082 RP2D was determined as 600mg. KRAS G12D protein degradation correlated with drug exposure by AUC with tumor shrinkage paralleling protein degradation (R=−0.514; p=0.0102). In pts with ≥50% reduced KRAS G12D VAF, 78% achieved stable disease (SD) or partial response (PR) and showed a clinical benefit. BL tumor KRAS G12D VAF was higher in pts with progressive disease (PD) vs SD/PR. BL serum CA19-9 and CEA were higher in pts with PD vs SD/PR but did not provide prognostic value beyond KRAS G12D VAF. Conclusions: ASP3082 induced robust KRAS G12D mutant protein degradation and inhibition of RAS-MAPK signaling in tumors. Findings indicate ctDNA KRAS G12D VAF is a prognostic and pharmacodynamic biomarker, supporting continued clinical development of ASP3082. Clinical trial information: NCT05382559 . KRAS G12D ≥50% ctDNA VAF reduction, n (%) BL KRAS tumor VAF, median (IQR) BL CA19-9 (U/mL), median (IQR) BL CEA (ng/mL),median (IQR) SD/PR 21/36 (58.3) 0.26 (0.07–2.6) 1824 (125–14296) 5.6 (3.05–14.8) PD 6/27 (22.2) 6.9 (0.94–27.7) 18455 (50–49363) 17.2 (7.3–88.2)