Clinical Trial

. 2025 Jun 17;10(1):189.

doi: 10.1038/s41392-025-02274-z.

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

Dan-Yun Ruan^#^{1

2}, Hao-Xiang Wu^#^{1

2}, Ye Xu³, Pamela N Munster⁴, Yanhong Deng⁵, Gary Richardson⁶, Dong Yan⁷, Myung-Ah Lee⁸, Keun-Wook Lee⁹, Hongming Pan¹⁰, Steven Hager¹¹, Xingya Li¹², Shaozhong Wei¹³, Xinfang Hou¹⁴, Craig Underhill¹⁵, Michael Millward¹⁶, Ina Nordman¹⁷, Jingdong Zhang¹⁸, Jianzhen Shan¹⁹, Guohong Han²⁰, Jaspreet Grewal²¹, Shirish M Gadgeel²², Rachel E Sanborn²³, Seok Jae Huh²⁴, Xiaohua Hu²⁵, Yihong Zhang²⁶, Ziyong Xiang²⁶, Laisheng Luo²⁶, Xiaoxi Xie²⁶, Zhe Shi²⁶, Yaolin Wang²⁶, Ling Zhang²⁶, Feng Wang^{27

28}, Rui-Hua Xu^{29

30}

Affiliations

¹ Department 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 University, Guangzhou, China.
² Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.
³ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Department of Medical Oncology, Cabrini Hospital - Malvern, Malvern, VIC, Australia.
⁷ Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China.
⁸ Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea.
⁹ Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹⁰ Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Medical Oncology Hematology, California Cancer Associates for Research and Excellence, Inc. (cCARE), Fresno, CA, USA.
¹² Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹³ Department of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, Wuhan, China.
¹⁴ Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, China.
¹⁵ Border Medical Oncology Research Unit, Albury Wodonga Regional Cancer Centre, Albury, NSW, Australia.
¹⁶ Linear Clinical Research & University of Western Australia, Perth, WA, Australia.
¹⁷ Medical Oncology Department, Calvary Mater Newcastle, Waratah, NSW, Australia.
¹⁸ Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Shenyang, China.
¹⁹ Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
²⁰ Department of Liver Diseases and Digestive Interventional Radiology, Xi'an International Medical Center Hospital, Xi'an, China.
²¹ Medical Oncology Hematology, Norton Cancer Institute, Louisville, KY, USA.
²² Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI, USA.
²³ Medical Oncology Department, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA.
²⁴ Division of Hematology-Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea.
²⁵ Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
²⁶ InventisBio Co. Ltd, Shanghai, China.
²⁷ Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. wangfeng@sysucc.org.cn.
²⁸ Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China. wangfeng@sysucc.org.cn.
²⁹ Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. xurh@sysucc.org.cn.
³⁰ Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China. xurh@sysucc.org.cn.

^# Contributed equally.

PMID: 40523897
PMCID: PMC12170901
DOI: 10.1038/s41392-025-02274-z

Clinical Trial

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

Dan-Yun Ruan et al. Signal Transduct Target Ther. 2025.

. 2025 Jun 17;10(1):189.

doi: 10.1038/s41392-025-02274-z.

Authors

Affiliations

¹ Department 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 University, Guangzhou, China.
² Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.
³ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁶ Department of Medical Oncology, Cabrini Hospital - Malvern, Malvern, VIC, Australia.
⁷ Department of Oncology, Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China.
⁸ Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, Cancer Research Institute, The Catholic University of Korea, Seoul, South Korea.
⁹ Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹⁰ Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Medical Oncology Hematology, California Cancer Associates for Research and Excellence, Inc. (cCARE), Fresno, CA, USA.
¹² Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
¹³ Department of Gastrointestinal Oncology Surgery, Hubei Cancer Hospital, Wuhan, China.
¹⁴ Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou, China.
¹⁵ Border Medical Oncology Research Unit, Albury Wodonga Regional Cancer Centre, Albury, NSW, Australia.
¹⁶ Linear Clinical Research & University of Western Australia, Perth, WA, Australia.
¹⁷ Medical Oncology Department, Calvary Mater Newcastle, Waratah, NSW, Australia.
¹⁸ Medical Oncology Department of Gastrointestinal Cancer, Liaoning Cancer Hospital & Institute, Shenyang, China.
¹⁹ Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
²⁰ Department of Liver Diseases and Digestive Interventional Radiology, Xi'an International Medical Center Hospital, Xi'an, China.
²¹ Medical Oncology Hematology, Norton Cancer Institute, Louisville, KY, USA.
²² Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI, USA.
²³ Medical Oncology Department, Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA.
²⁴ Division of Hematology-Oncology, Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea.
²⁵ Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
²⁶ InventisBio Co. Ltd, Shanghai, China.
²⁷ Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. wangfeng@sysucc.org.cn.
²⁸ Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China. wangfeng@sysucc.org.cn.
²⁹ Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China. xurh@sysucc.org.cn.
³⁰ Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, China. xurh@sysucc.org.cn.

^# Contributed equally.

PMID: 40523897
PMCID: PMC12170901
DOI: 10.1038/s41392-025-02274-z

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.

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Conflict of interest statement

Competing interests: K-W.L. disclosed institutional research funding (to the institution) from InventisBio for conducting the clinical trial related to this report; research funding (to the institution; outside of the submitted work) for conducting clinical trials from AstraZeneca, Merck Sharp and Dohme, ONO pharmaceutical, Merck KGaA, Roche, BeiGene, Leap therapeutics, ALX Oncology, Zymeworks, Astellas, Macrogenics, Amgen, Seagen, Bolt therapeutics, Trishula therapeutics, MedPacto, Green Cross Corp, Y-BIOLOGICS, Daiichi Sankyo, Taiho Pharmaceutical, Elevar Therapeutics, Metafines, Idience, Genome & Company, Exelixis, Panolos Bioscience; has participated on data safety monitoring boards or advisory boards for ALX Oncology and Metafines; has received consulting fees from Daiichi Sankyo, Merck Sharp and Dohme, Astellas, Bayer (outside the submitted work); and honoraria for lectures or presentation from Merck KGaA, Daiichi Sankyo, Astellas, Sanofi-Aventis (outside the submitted work). M.M. reports study payments from InventisBio; reports consulting fees from Roche, Bristol-Myers Squibb, AstraZeneca, Pfizer, Merck Serono, Guardant Health, The Limbic, Beigene, Amgen, Merck, IQVIA, and Eli Lilly, participates on a Data Safety Monitoring Board or Advisory Board for Novartis. S.M.G. reports consulting fees from Pfizer, Takeda, Boehringer-Ingelheim, Astra-Zeneca, Genentech/Roche, Daichii, Abbvie, Arcus, Blueprint, Mirati, Merck, Esai, Lilly, Novartis, Bayer, Gilead; reports support for attending meetings and/or travel from Merck, Mirati; participates on advisory board for Astra-Zeneca. R.E.S. reports grants or contracts from AstraZeneca and Merck; reports consulting fees from GlaxoSmithKline, AstraZeneca, Janssen Oncology, Macrogenics, Daiichi, Sanofi, BeiGene, Gilead, Regeneron, Targeted Oncology, G1 Therapeutics, GE HealthCare, Amgen, and Lilly Oncology; reports Payment or honoraria for lectures, presentations from EMD Serono, Illumina, GameOn!, OncLive, Binay Foundation, APP Oncology, and Masters in Thoracic Oncology Summit; participates on advisory board for GlaxoSmithKline, AstraZeneca, Janssen Oncology, Macrogenics, Daiichi, Sanofi, BeiGene, Gilead, Regeneron, Targeted Oncology, G1 Therapeutics, GE HealthCare, Amgen, and Lilly Oncology. Y.Z., L.L. and X.X. report InventisBio employment. Z.X., Z.S., Y.W. and L.Z. report InventisBio employment and stock. R.-H.X. reports speaker fees from Bristol Myers Squibb, Roche, MerckSerono, Hutchison, Hengrui, Junshi, Qilu, CPPC, Henlius, and participates on advisory board for Astellas, MSD, AstraZeneca, Junshi, Hengrui, BeiGene. Innovent, CPPC, and Keymed. All other authors declare no competing interests.

Figures

**Fig. 2**
Efficacy outcomes with garsorasib monotherapy. a Best tumor response and tumor burden change from baseline. b Swimmer plot of time to response, treatment duration. c Kaplan-Meier estimates of progression-free survival

**Fig. 3**
Efficacy outcomes with garsorasib plus cetuximab. a Best tumor response and tumor burden change from baseline. b Swimmer plot of time to response, treatment duration. c Kaplan-Meier estimates of progression-free survival

See this image and copyright information in PMC

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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

Affiliations

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

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