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<p><i>KRAS</i><sup>G12D</sup> 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 <i>KRAS</i><sup>G12D</sup>-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 <i>KRAS</i><sup>G12D</sup>-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: <a href="https://clinicaltrials.gov/study/NCT06520488?term=NCT06520488&amp;viewType=Card&amp;rank=1">NCT06520488</a>.</p>

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KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRASG12D-mutant pancreatic cancer: a phase 1b/2 trial

  • 期刊论文

  • 发表日期：

    2026年7月9日

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  • Jiujie Cui,
  • Kuirong Jiang,
  • Wei Li,
  • Shuqin Ni,
  • Hong Zong,
  • Juan Du,
  • Yifu He,
  • Zhonghua Liu,
  • Guoqiang Kong,
  • Yanqiao Zhang,
  • Xiaotong Li,
  • Hongxia Han,
  • Fen Yao,
  • Yongwu Chen,
  • Ming Zhou,
  • Liwei Wang

摘要

KRASG12D 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 KRASG12D-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 KRASG12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488.