SHR-A2102, a Nectin-4 targeted antibody-drug conjugate, combined with HRS-4642 in previously treated pancreatic ductal adenocarcinoma harboring KRAS G12D mutation.

4191 Background: Patients (pts) with previously treated advanced pancreatic ductal adenocarcinoma (PDAC) have limited options. The high prevalence of Nectin-4 expression (~71%) and KRAS G12D mutations in PDAC provides a rationale for dual targeting. Here we report results from a molecularly defined cohort in a phase 2 platform trial evaluating the combination of SHR-A2102 and HRS-4642, a KRAS G12D inhibitor. Methods: Eligible pts with Nectin-4 expression and KRAS G12D mutation who had failed standard therapy were enrolled. During the safety run-in, 2 dose levels of SHR-A2102 were evaluated in combination with HRS-4642 (500mg Day 1/1200mg Day 8, iv, q3w) to determine the recommended expansion dose (RED). The Bayesian Optimal Phase II (BOP2) design was applied for efficacy expansion, with a planned enrollment of 10 to 30 pts. The primary endpoints were safety and RED (safety run-in), and objective response rate (ORR; efficacy expansion). The key secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DoR), and disease control rate (DCR). Results: As of Dec. 31, 2025, 36 pts were enrolled and treated (median age, 61 years; ECOG PS 1, 86.1%; ≥2 lines of prior therapy, 88.9%; median Nectin-4 H-score, 10). No dose-limiting toxicity (DLT) occurred, and the RED was established as SHR-A2102 (8mg/kg iv, q3w) plus HRS-4642. Treatment-related adverse events (TRAEs) occurred in all pts (100%), with no grade 5 TRAEs. 13 pts (36.1%) experienced grade 3/4 TRAEs, the most common including neutrophil count decreased and gamma-glutamyl transpeptidase increased (each 11.1%), and anemia (8.3%). In the RED group (n=30), the confirmed ORR was 36.7% (11PR) and the DCR was 86.7%, meeting the primary endpoint. ORR showed no apparent correlation with Nectin-4 H-score. The median DoR was 6.3 months (range: 4.4-NR); the median PFS was 4.1 months (range: 2.7-5.7), and the median OS was not reached. Conclusions: SHR-A2102 combined with HRS-4642 showed a tolerable safety profile and promising preliminary anti-tumor activity in advanced PDAC harboring KRAS G12D mutation, irrespective of Nectin-4 expression. Clinical trial information: NCT06547736 .