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Updated: Jan 22, 2026

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRASG12D

Ling Xie1,2, Chunwei Xu2, Han Si1

  • 1Phase I Clinical Trial Ward, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.

Cancer Discovery
|January 20, 2026
PubMed

Insights

RNK08954 shows promise as a KRAS G12D inhibitor for solid tumors. Early clinical trials indicate significant tumor response rates in non-small cell lung cancer and pancreatic cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS G12D mutations are common in solid tumors, yet lack targeted therapies.
  • RNK08954 is a novel, potent, and selective inhibitor targeting KRAS G12D.
  • Preclinical studies show RNK08954 inhibits cancer cell proliferation and tumor growth.

Purpose of the Study:

  • To evaluate the safety and efficacy of RNK08954 in patients with KRAS G12D-mutant solid tumors.
  • To assess the pharmacokinetic profile and tumor retention of RNK08954.
  • To explore the combination therapy of RNK08954 with immune checkpoint blockade (ICB).

Main Methods:

  • Phase 1a clinical trial involving 36 evaluable patients with KRAS G12D mutations.
  • Pharmacokinetic analysis and assessment of tumor regression in mouse xenograft models.
  • Evaluation of objective response rates (ORR) in non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) cohorts.

Main Results:

  • RNK08954 demonstrated significant tumor regressions in preclinical models.
  • In NSCLC patients, an unconfirmed ORR of 58.33% was observed.
  • In PDAC patients (1000-1200mg cohort), an unconfirmed ORR of 33.33% was reported.
  • RNK08954 exhibits a favorable pharmacokinetic profile with prolonged tumor retention.
  • Synergistic effects were observed when combined with immune checkpoint blockade.

Conclusions:

  • RNK08954 exhibits potent anti-tumor activity against KRAS G12D-mutant cancers.
  • The drug shows promising preliminary efficacy in NSCLC and PDAC.
  • RNK08954 supports clinical development as a monotherapy or in combination for KRAS G12D-driven malignancies.

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