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).
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). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRAS G12D -mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488 .
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Data can be made available under restricted access due to proprietary reasons. Individual de-identified patient data generated during this study will be considered for sharing after the product and indication have been approved by major health authorities. Data may be requested 24 months after study completion. Qualified researchers should submit a proposal to the corresponding author outlining the reasons for requiring the data. The leading clinical site and sponsor will respond to requests within approximately 8 weeks. The sponsor will provide the data if the proposal is approved, provided that the requestor signs a data access agreement. The use of data must comply with the requirements of the Human Genetics Resources Administration of China and other applicable country- or region-specific regulations. The study protocol and statistical analysis plan are provided in Supplementary Information .
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