Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials

Jian Li; Ting Deng; Yanhong Gu; Antonio Calles Blanco; Zhihua Li; Chunmei Bai; Lin Wu; Jing Huang; Xingya Li; Yu Yao; Zhengbo Song; Yongsheng Li; Lian Liu; Ligang Xing; Wenming Wu; Julia Martínez-Pérez; Ayala Hubert; Jon Zugazagoitia; Jian Zhang; Yongsheng Wang; Yanqiu Zhao; Guilan Wen; Guohao Xia; Diansheng Zhong; Xueqin Chen; Kuirong Jiang; Andrea Wang-Gillam; Yuli Ding; Sumei Liu; Zhiyue Rao; Xinghu Liu; Lin Shen

doi:10.1002/cac2.70056

Cancer Communications ›› 2025, Vol. 45 ›› Issue (11) :1500 -1512. DOI: 10.1002/cac2.70056

ORIGINAL ARTICLE

Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials

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¹. Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing Cancer Hospital, Beijing, P. R. China

². Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, P. R. China

³. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P. R. China

⁴. Department of Medical Oncology, Hospital General Universitario Gregorio Marañon, Madrid, Spain

⁵. Department of Medical Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, P. R. China

⁶. Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, P. R. China

⁷. Department of Thoracic Medical Oncology, Hunan Cancer Hospital, Changsha, Hunan, P. R. China

⁸. Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, P. R. China

⁹. Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, P. R. China

¹⁰. Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P. R. China

¹¹. Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, P. R. China

¹². Department of Medical Oncology, Chongqing Cancer Hospital, Chongqing, P. R. China

¹³. Department of Medical Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China

¹⁴. Department of Radiation Oncology, Shandong Cancer Hospital, Jinan, Shandong, P. R. China

¹⁵. Department of Medical Oncology, Hospital Universitario Virgen del Rocio – PPDS, Sevilla, Spain

¹⁶. Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

¹⁷. Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain

¹⁸. Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, P. R. China

¹⁹. Department of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan, P. R. China

²⁰. Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, Henan, P. R. China

²¹. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, P. R. China

²². Department of Oncology, Jiangsu Cancer Hospital, Nanjing, Jiangsu, P. R. China

²³. Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, P. R. China

²⁴. Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, P. R. China

²⁵. Jacobio (US) Pharmaceutical, Inc., Burlington, Massachusetts, USA

²⁶. Jacobio Pharmaceuticals Co., Ltd., Beijing, P. R. China

oncogene@163.com

linshenpku@163.com

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Abstract

Background: Glecirasib, an inhibitor of Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine substitution at codon 12 (KRAS G12C), has exhibited clinical activity in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we investigated the efficacy and safety of glecirasib in patients with pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (excluding NSCLC and CRC) that rarely harbor the KRAS G12C mutation but for which effective treatment options remain limited.

Methods: We conducted and analyzed two open-label, phase I/II trials in adult patients with KRAS G12C mutant solid tumors, in which glecirasib was administered orally. The two trials had similar eligibility criteria and endpoints but differed in the regions of patient recruitment. We performed a pooled analysis of all patients, excluding NSCLC and CRC, from both trials. The primary endpoint in the pooled population was objective response rate (ORR). Efficacy and safety were assessed in patients who received at least one dose of glecirasib.

Results: As of June 30, 2024, the pooled analysis included 54 patients who were treated with glecirasib: 32 PDACs, 8 biliary tract cancers (BTCs), 4 small intestinal cancers, 3 gastric cancers, 2 appendiceal cancers, and 5 other tumors. At baseline, 24 received ≥ two prior lines of systemic therapy. Of the 53 efficacy-evaluable patients, the confirmed ORR was 50.9% (95% confidence interval [CI], 36.8%-64.9%), with an ORR of 46.9% (95% CI, 29.1%-65.3%) in PDAC patients. Among other solid tumors, ORR was 71.4% (5/7) in BTC, 100% (4/4) in small intestinal cancer, and 66.7% (2/3) in gastric cancer. Median progression-free survival and median overall survival were 6.9 and 10.8 months, respectively, in the overall population, and 5.5 and 10.8 months, respectively, in patients with PDAC. Treatment-related adverse events (TRAEs) of any grade occurred in 94.4% patients, with grade ≥ 3 TRAEs in 27.8%. No fatal TRAEs or TRAEs leading to treatment discontinuation occurred.

Conclusions: Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population.

Trial registration: ClinicalTrials.gov identifier: NCT05009329 and NCT05002270.

Keywords

biliary tract cancer / glecirasib / JAB-21822 / KRAS G12C / pancreatic cancer / small intestinal cancer

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Jian Li, Ting Deng, Yanhong Gu, Antonio Calles Blanco, Zhihua Li, Chunmei Bai, Lin Wu, Jing Huang, Xingya Li, Yu Yao, Zhengbo Song, Yongsheng Li, Lian Liu, Ligang Xing, Wenming Wu, Julia Martínez-Pérez, Ayala Hubert, Jon Zugazagoitia, Jian Zhang, Yongsheng Wang, Yanqiu Zhao, Guilan Wen, Guohao Xia, Diansheng Zhong, Xueqin Chen, Kuirong Jiang, Andrea Wang-Gillam, Yuli Ding, Sumei Liu, Zhiyue Rao, Xinghu Liu, Lin Shen. Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials. Cancer Communications, 2025, 45(11): 1500-1512 DOI:10.1002/cac2.70056

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