Multicenter phase 1b-2 trial of HRS-4642 plus chemotherapy for advanced KRAS-G12D-mutant pancreatic cancer

KRAS^G12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inibitors are oral small molecules limited by gastrointestinal toxicities and suboptimal tumor exposure, HRS-4642 is a new, high-affinity, noncovalent KRAS-G12D inhibitor. Formulated as a liposomal nanoparticle for intravenous administration, it is designed to enhance tumor accumulation and prolong the duration of target inhibition. A multicenter phase 1b-2 study in China evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRAS^G12D-mutant PDAC.Thirty-one patients (one previously treated and 30 treatment-naïve patients) were enrolled and treated. In phase 1b, no dose-limiting toxicities were observed, and 500 mg on day 1 and 1200 mg on day 8 every 3 weeks was selected as the recommended phase 2 dose. In phase 2, with a median follow-up of 12.3 months, the confirmed objective response rate in treatment-naïve patients was 63.3% (95% CI 43.9-80.1), meeting the primary endpoint. Grade ≥ 3 treatment-related adverse events occurred in 90.3% of patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. The authors conclude that HRS-4642 combined with AG demonstrated promising antitumor activity and a manageable safety profile in patients with advanced KRAS^G12D-mutant PDAC.