Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRASG12D Inhibitor

  • Cancer Discov. 2026 May 1;16(5):895-910. doi: 10.1158/2159-8290.CD-25-1346.
Ling Xie  #  1  2 ,  Chunwei Xu  #  2 ,  Han Si  #  1 ,  Xiaoshuang Fu  #  1 ,  Xiangcai Yang  #  3 ,  Jianan Jin  1 ,  Xiaoqing Yu  1 ,  Zhiying Shao  1 ,  Yanling Wang  1 ,  Tianqing Chu  4 ,  Jun Zhang  5 ,  Rong Liang  6 ,  Rui Meng  7 ,  Yuchen Fei  1 ,  Haolin Song  1 ,  Chenghao Ying  3 ,  Yan Dai  3 ,  Yaya Wang  3 ,  Iman Ei-Hariry  3 ,  Guoqiang Wang  3 ,  Weiwen Ying  3 ,  Zhengbo Song  1  2
Affiliations
  • 1. Phase I Clinical Trial Ward, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
  • 2. Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
  • 3. Ranok Therapeutics (Hangzhou), Inc., Hangzhou, China.
  • 4. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5. Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China.
  • 7. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • # Contributed equally.
PMID: 41557983 DOI: 10.1158/2159-8290.CD-25-1346
Abstract

KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRASG12D inhibitor that inhibits proliferation of KRASG12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune checkpoint blockade (ICB). In a phase Ia study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung Cancer (NSCLC), the objective response rate (ORR; unconfirmed) was 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC), the ORR (unconfirmed) was 33.33% in the 1,000- to 1,200-mg cohort. This study supports the clinical potential of RNK08954 in patients with KRASG12D mutation either as a single agent or in combination.

Significance: RNK08954 is potentially the first orally bioavailable KRASG12D inhibitor, distinguished by unique PK properties, preclinical efficacy, preliminary clinical activity with encouraging results in patients with NSCLC and PDAC, and synergistic potential with ICB. RNK08954 may address a critical unmet need by targeting the most prevalent KRAS mutation across solid tumors.

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