Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation
Abstract Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the “undruggable” challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti...
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2025-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02274-z |
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| author | Dan-Yun Ruan Hao-Xiang Wu Ye Xu Pamela N. Munster Yanhong Deng Gary Richardson Dong Yan Myung-Ah Lee Keun-Wook Lee Hongming Pan Steven Hager Xingya Li Shaozhong Wei Xinfang Hou Craig Underhill Michael Millward Ina Nordman Jingdong Zhang Jianzhen Shan Guohong Han Jaspreet Grewal Shirish M. Gadgeel Rachel E. Sanborn Seok Jae Huh Xiaohua Hu Yihong Zhang Ziyong Xiang Laisheng Luo Xiaoxi Xie Zhe Shi Yaolin Wang Ling Zhang Feng Wang Rui-Hua Xu |
| author_facet | Dan-Yun Ruan Hao-Xiang Wu Ye Xu Pamela N. Munster Yanhong Deng Gary Richardson Dong Yan Myung-Ah Lee Keun-Wook Lee Hongming Pan Steven Hager Xingya Li Shaozhong Wei Xinfang Hou Craig Underhill Michael Millward Ina Nordman Jingdong Zhang Jianzhen Shan Guohong Han Jaspreet Grewal Shirish M. Gadgeel Rachel E. Sanborn Seok Jae Huh Xiaohua Hu Yihong Zhang Ziyong Xiang Laisheng Luo Xiaoxi Xie Zhe Shi Yaolin Wang Ling Zhang Feng Wang Rui-Hua Xu |
| author_sort | Dan-Yun Ruan |
| collection | DOAJ |
| description | Abstract Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the “undruggable” challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials. We conducted an open-label, nonrandomized phase II trial (ClinicalTrials.gov, NCT04585035) to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC. In the monotherapy cohort (n = 26), objective response rate (ORR) was 19.2% (95% CI, 6.6–39.4), disease control rate (DCR) was 92.3% (95% CI, 74.9–99.1), median progression-free survival (PFS) was 5.5 months (95% CI, 2.9–11.6) and median overall survival (OS) was 13.1 months (95% CI, 9.5-NE). In the combination cohort (n = 42), ORR was 45.2% (95% CI, 29.8–61.3), DCR was 92.9% (95% CI, 80.5–98.5), median PFS was 7.5 months (95% CI, 5.5–8.1), and median OS was not reached. Grade ≥3 treatment-related adverse events occurred in 5 (19.2%) and 6 (14.3%) patients in monotherapy and combination cohort, respectively. Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC, providing a potential new treatment approach for such population. |
| format | Article |
| id | doaj-art-dbf9082e89c74c00b26856bb698529aa |
| institution | OA Journals |
| issn | 2059-3635 |
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| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-dbf9082e89c74c00b26856bb698529aa2025-08-20T02:10:38ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-06-011011910.1038/s41392-025-02274-zGarsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutationDan-Yun Ruan0Hao-Xiang Wu1Ye Xu2Pamela N. Munster3Yanhong Deng4Gary Richardson5Dong Yan6Myung-Ah Lee7Keun-Wook Lee8Hongming Pan9Steven Hager10Xingya Li11Shaozhong Wei12Xinfang Hou13Craig Underhill14Michael Millward15Ina Nordman16Jingdong Zhang17Jianzhen Shan18Guohong Han19Jaspreet Grewal20Shirish M. Gadgeel21Rachel E. Sanborn22Seok Jae Huh23Xiaohua Hu24Yihong Zhang25Ziyong Xiang26Laisheng Luo27Xiaoxi Xie28Zhe Shi29Yaolin Wang30Ling Zhang31Feng Wang32Rui-Hua Xu33Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen UniversityDepartment of Colorectal Surgery, Fudan University Shanghai Cancer CenterDepartment of Medicine, University of California San FranciscoDepartment of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen UniversityDepartment of Medical Oncology, Cabrini Hospital - MalvernDepartment of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical UniversityDivision of Medical Oncology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, Cancer Research Institute, The Catholic University of KoreaSeoul National University College of Medicine, Seoul National University Bundang HospitalDepartment of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineMedical Oncology Hematology, California Cancer Associates for Research and Excellence, Inc. (cCARE)Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Gastrointestinal Oncology Surgery, Hubei Cancer HospitalDepartment of Medical Oncology, Henan Cancer HospitalBorder Medical Oncology Research Unit, Albury Wodonga Regional Cancer CentreLinear Clinical Research & University of Western AustraliaMedical Oncology Department, Calvary Mater NewcastleMedical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & InstituteDepartment of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of MedicineDepartment of Liver Diseases and Digestive Interventional Radiology, Xi’an International Medical Center HospitalMedical Oncology Hematology, Norton Cancer InstituteDivision of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health SystemMedical Oncology Department, Earle A. Chiles Research Institute, Providence Cancer InstituteDivision of Hematology-Oncology, Department of Internal Medicine, Dong-A University College of MedicineDepartment of Medical Oncology, The First Affiliated Hospital of Guangxi Medical UniversityInventisBio Co. LtdInventisBio Co. LtdInventisBio Co. LtdInventisBio Co. LtdInventisBio Co. LtdInventisBio Co. LtdInventisBio Co. LtdResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesResearch Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesAbstract Mutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the “undruggable” challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials. We conducted an open-label, nonrandomized phase II trial (ClinicalTrials.gov, NCT04585035) to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC. In the monotherapy cohort (n = 26), objective response rate (ORR) was 19.2% (95% CI, 6.6–39.4), disease control rate (DCR) was 92.3% (95% CI, 74.9–99.1), median progression-free survival (PFS) was 5.5 months (95% CI, 2.9–11.6) and median overall survival (OS) was 13.1 months (95% CI, 9.5-NE). In the combination cohort (n = 42), ORR was 45.2% (95% CI, 29.8–61.3), DCR was 92.9% (95% CI, 80.5–98.5), median PFS was 7.5 months (95% CI, 5.5–8.1), and median OS was not reached. Grade ≥3 treatment-related adverse events occurred in 5 (19.2%) and 6 (14.3%) patients in monotherapy and combination cohort, respectively. Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC, providing a potential new treatment approach for such population.https://doi.org/10.1038/s41392-025-02274-z |
| spellingShingle | Dan-Yun Ruan Hao-Xiang Wu Ye Xu Pamela N. Munster Yanhong Deng Gary Richardson Dong Yan Myung-Ah Lee Keun-Wook Lee Hongming Pan Steven Hager Xingya Li Shaozhong Wei Xinfang Hou Craig Underhill Michael Millward Ina Nordman Jingdong Zhang Jianzhen Shan Guohong Han Jaspreet Grewal Shirish M. Gadgeel Rachel E. Sanborn Seok Jae Huh Xiaohua Hu Yihong Zhang Ziyong Xiang Laisheng Luo Xiaoxi Xie Zhe Shi Yaolin Wang Ling Zhang Feng Wang Rui-Hua Xu Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation Signal Transduction and Targeted Therapy |
| title | Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation |
| title_full | Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation |
| title_fullStr | Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation |
| title_full_unstemmed | Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation |
| title_short | Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation |
| title_sort | garsorasib a kras g12c inhibitor with or without cetuximab an egfr antibody in colorectal cancer cohorts of a phase ii trial in advanced solid tumors with kras g12c mutation |
| url | https://doi.org/10.1038/s41392-025-02274-z |
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