HRS-4642 plus chemotherapy shows promising tumor response in pancreatic cancer.
KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRAS G12D -mutant pancreatic cancer: a phase 1b/2 trial.
Jiujie Cui et al. · Nature medicine · 2026
Background
KRAS G12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC).
Methods
As of 5 December 2025,68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated.
n = 68 patients
63.3%
Results
More than half of patients saw their pancreatic cancer tumors shrink or disappear
n = 68 patients
More results
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.
This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRAS G12D -mutant PDAC.
More results
Grade ≥3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy.
Clinicaltrials.gov registration: NCT06520488 .
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Conclusion
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.