Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRAS inhibitor-naïve Chinese patients with KRAS-mutated metastatic colorectal cancer: a pooled analysis from phase I part of two studies.

Lian Liu, Dongde Wu, Zhiye Zhang, Xiangjiao Meng, Dong Hua, Zhiwu Wang, Cunji Wang, Huijuan Wang, Ying Yuan, Yi Hu, Xiaoyan Li, Mengna Huang, Kefeng Ding, Jingjing Huang, Mingjun Zhang, Yongdong Jin, Zengqing Guo, Xiuwen Wang, Meili Sun, Sujie Zhang, Yanhong Deng, Nong Yang, Sheng Hu, Dingzhi Huang, Yueyin Pan, Mingfang Zhao, Xiaorong Dong

Journal: Signal transduction and targeted therapy 2025;10(1):241

PMID: 40715048

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Abstract

IBI351 (also known as fulzerasib or GFH925), an irreversible covalent inhibitor of KRAS, has demonstrated promising anti-tumour activity in patients with solid tumours. In this study, data were pooled from the phase I part of two clinical studies (NCT05005234 and NCT05497336), aiming to evaluate the efficacy and safety of IBI351 monotherapy in KRAS inhibitor-naïve Chinese patients with KRAS-mutated metastatic colorectal cancer (CRC). The objective response rate (ORR) was the primary endpoint. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). As of December 13, 2023, 56 patients treated with IBI351 monotherapy were included. The median duration of treatment was 7.7 months (range: 0.3-16.7). The confirmed ORR was 44.6% (95% CI: 31.3-58.5), with a DCR of 87.5% (95% CI: 75.9-94.8). With a median follow-up of 13.8 months, the median PFS was 8.1 months (95% CI: 5.5-13.8). The median OS was 17.0 months (95% CI: 12.6-not reached). Treatment-related adverse events (TRAEs) occurred in 53 patients (94.6%), with grade 3 TRAEs in 14 patients (25.0%). No grade 4 or 5 TRAEs were observed. The most common grade 3 TRAEs were anaemia (n = 4, 7.1%) and gamma-glutamyltransferase increased (n = 3, 5.4%). TRAEs led to dose interruption in 12 patients (21.4%) and dose reduction in six patients (10.7%). No TRAEs resulted in treatment discontinuation. IBI351 demonstrated encouraging clinical efficacy and a manageable safety profile in KRAS inhibitor-naïve Chinese patients with KRAS-mutated metastatic CRC.

Address: Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.; Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.; Department of Medical Oncology, Sichuan Cancer Hospital, Chengdu, China.; Department of Special Demand Ward/Department of Clinical Nutrition, Fujian Cancer Hospital, Fuzhou, China.; Department of Tumor Chemotherapy, Anhui Provincial Hospital, Hefei, China.; Department of Oncology, Hunan Traditional Chinese Medical College No.1 Affiliated Hospital, Zhuzhou, China.; The Second Department of Radiochemotherapy, Tangshan People's Hospital, Tangshan, China.; Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.; Department of Oncology, Wuxi People's Hospital, Wuxi, China.; Thoracic Radiation Oncology Ward IV, Shandong Provincial Cancer Hospital, Jinan, China.; Department of Medical Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China.; Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.; Department of Thoracic Oncology, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.; Department of Pulmonary Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.; Department of Medical Oncology, Beijing Tiantan Hospital of Capital Medical University, Beijing, China.; Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, China.; Department of Medical Oncology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.; Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China.; Department of Medical Oncology, Qilu Hospital of Shandong University (Qingdao), Qingdao, China.; Department of Pulmonary Gastroenterology, The Second People's Hospital of Hunan Province, Changsha, China.; Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.; Hepatopancreatobiliary Surgery Department, Hubei Cancer Hospital, Wuhan, China.; Innovent Biologics Co., Ltd., Suzhou, China.; Department of Colorectal Surgery and Oncology, Center for Medical Research and Innovation in Digestive System Tumors, Ministry of Education, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].

DOI: 10.1038/s41392-025-02315-7

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MeSH Terms: Humans, Colorectal Neoplasms, Male, Middle Aged, Female, Proto-Oncogene Proteins p21(ras), Aged, Adult, Mutation, Neoplasm Metastasis, Asian People, East Asian People