HRS-4642 combined with adebrelimab in previously treated patients with metastatic pancreatic ductal adenocarcinoma.

Abstract

4190 Background: Nearly 90% pancreatic ductal adenocarcinoma (PDAC) tumors were driven by RAS mutations, including KRAS G12D (~40%). The high prevalence of KRAS G12D mutations is thought to play a vital role in the universally immunosuppressive tumor microenvironment of PDAC. HRS-4642 is a highly selective KRAS G12D inhibitor. Here, we report preliminary results of HRS-4642 combined with adebrelimab (an anti-PD-L1 antibody) in patients (pts) with KRAS G12D-mutant PDAC. Methods: The study comprised two parts. Phase 1 (Dose escalation): A “3+3” design was used to determine the recommended phase 2 dose (RP2D) of HRS-4642 (4 dose levels: 300, 400, 500mg, qw; and 500mg D1/1200mg D8, q3w) combined with fixed-dose adebrelimab (1200mg iv, Day 1, q3w). Phase 2 (Dose expansion): Simon's two-stage optimal design was applied, requiring at least five objective responses. The primary endpoints were safety and RP2D (phase 1), and objective response rate (ORR; phase 2). The key secondary endpoints included progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). Results: As of Dec 31, 2025, 48 pts were enrolled, with 87.5% having received ≥2 prior lines of therapy. No dose-limiting toxicity (DLT) occurred during phase 1, and the RP2D was determined as HRS-4642 (500mg D1/1200mg D8, q3w) with adebrelimab. Treatment-related adverse events (TRAEs) occurred in 47 pts (97.9%). The most common grade 3/4 TRAEs included lipase increased (16.7%), gamma-glutamyl transpeptidase increased (12.5%), and blood cholesterol increased (8.3%). No treatment related deaths occurred. Among 43 pts with post-baseline tumor assessment, the confirmed ORR was 41.9% and DCR was 83.7%, with a median mPFS of 5.6 months; the median mOS was not reached. Notably, the RP2D group (n=33) achieved a confirmed ORR of 48.5% and a DCR of 90.9%, successfully meeting the primary endpoint. Conclusions: HRS-4642 combined with adebrelimab showed a manageable safety profile and promising anti-tumor activity in metastatic PDAC harboring KRAS G12D mutation. Clinical trial information: NCT06427239 . Efficacy Evaluation. All (n=43) RP2D (n=33) Objective response, n (%) 18 (41.9) 16 (48.5) Best response, n (%) Partial Response 18 (41.9) 16 (48.5) Stable Disease 18 (41.9) 14 (42.4) Progressive Disease 7 (16.3) 3 (9.1) Disease control rate, n (%) 36 (83.7) 30 (90.9) Median progression-free survival, months (95%CI) 5.6 (4.0-7.3) 5.9 (4.2-7.9) Median overall survival, months (95%CI) NR 11.5 (9.2-NR)