Efficacy and safety of ASP3082 monotherapy or in combination with mFOLFIRINOX in patients (pts) with pancreatic ductal adenocarcinoma (PDAC).

Abstract

704 Background: KRAS G12D mutations occur in ~40% of pts with PDAC and are linked to poor prognosis. ASP3082, a first-in-class protein degrader targeting KRAS G12D, showed a manageable safety profile and promising antitumor activity in pts with KRAS G12D-mutant PDAC in a Phase 1 study (NCT05382559). We present results from this first-in-human study in pts with PDAC, including dose escalation and expansion, treated with ASP3082 or ASP3082 with modified folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin (mFOLFIRINOX). Methods: Adults with previously treated locally advanced or treatment-naïve metastatic PDAC with documented KRAS G12D, ECOG PS score 0–1, and measurable disease by RECIST v1.1 were included. Pts received ASP3082 monotherapy at 300mg or 600mg IV once weekly or ASP3082+mFOLFIRINOX. Primary endpoint was safety. Secondary endpoints were objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and ASP3082 pharmacodynamics/pharmacokinetics. Results: Data cutoff (DCO) was February 23, 2025. In the dose-ranging safety analysis set, ASP3082 300mg or 600mg were each given to 20 pts with PDAC. Median prior lines of systemic anticancer therapy was 2 (range, 1–4) for both doses. Treatment-related adverse events (TRAEs) were reported in 16/20 (80%) pts at 300mg and 17/20 (85%) pts at 600mg. Most common TRAEs for 300mg and 600mg, respectively, were pruritus (35%, 30%) and urticaria (20%, 25%), mainly due to infusion-related reactions (IRRs); and nausea (20%, 35%). IRRs were all grades 1–2 and manageable with a short dose infusion pause. No pts experienced TRAEs of grade ≥3 or that resulted in treatment discontinuation. Median relative dose intensity at 600mg was 98.5%. In pts receiving ASP3082 as second- or third-line (2L/3L) with ≥1 post-baseline scan in the dose-ranging expansion cohorts, ORR was 23.1% (95% CI: 5.0%, 53.8%) at 600mg and 0% at 300mg. Based on clinical efficacy, exposure-efficacy analysis, and dose-dependent KRAS G12D protein degradation, the recommended Phase 2 dose for ASP3082 monotherapy is 600mg. Of 18 pts (dose escalation + expansion) receiving ASP3082 600mg monotherapy as 2L (n=5) or 3L (n=13) with ≥1 post-baseline scan, ORR was 27.8% (95% CI: 9.7%, 53.5%); 5 pts had confirmed PRs. DCR was 66.7% (95% Cl: 41.0%, 86.7%). In the first-line (1L) metastatic PDAC cohort (DCO, June 25, 2025), 6 pts received ≥1 cycle of ASP3082+mFOLFIRINOX; 3 pts had grade 3 TRAEs (anemia, nausea, neutropenia; n=1 each). There were no DLTs. Five pts were evaluated for efficacy; 3 had confirmed PRs and 2 had stable diseases. Conclusions: ASP3082 showed promising antitumor activity alone or plus mFOLFIRINOX with no new safety signals in pts with PDAC. Findings support further evaluation of ASP3082 including DOR, progression-free survival, and overall survival in pts with KRAS G12D-mutant PDAC in both 1L and later-line settings. Clinical trial information: NCT05382559 .