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KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRAS G12D -mutant pancreatic cancer: a phase 1b/2 trial

Nature Medicine, Published online: 09 July 2026; doi:10.1038/s41591-026-04538-9 In phase 1b/2 trial, the treatment of patients with metastatic KRASG12D-mutant pancreatic cancer, t

GIST

KRAS G12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inhibitors 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. This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRAS G12D -mutant PDAC. As of 5 December 2025, 68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated. In the phase 1b portion, no dose-limiting toxicities were observed, and the starting dose (500 mg on day 1 and 1,200 mg on day 8, every 3 weeks) was selected as the recommended phase 2 dose. In the phase 2 portion, with a median follow-up of 12.3 months (95% confidence interval (CI) = 12.2–13.0), the primary endpoint was met—the confirmed objective response rate in 30 treatment-naive patients was 63.3% (95% CI = 43.9–80.1).

Clinical Editorial

Nature Medicine published a clinical update in Research Highlights on 09 Jul 2026. The item focuses on KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRAS G12D -mutant pancreatic cancer: a phase 1b/2 trial. Review the original article for the full source wording and details.

Original source: https://www.nature.com/articles/s41591-026-04538-9