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

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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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-06-16
DOI
https://doi.org/10.1038/s41392-025-02274-z
Citations
13
Primary Topic
Colorectal Cancer Treatments and Studies
Type
article
Field-Weighted Citation Impact
13.59
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article

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

Rachel E. Sanborn, Gary Richardson, Craig R. Underhill, Seok Jae Huh et al.
13 citations
Signal Transduction and Targeted Therapy
Colorectal Cancer Treatments and Studies
13.59
article

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

Rachel E. Sanborn, Gary Richardson, Craig R. Underhill, Seok Jae Huh, Laisheng Luo, Yaolin Wang, Michael Millward, Myung Ah Lee, Shirish M. Gadgeel, Hongming Pan, Zhe Shi, Guohong Han, Ye Xu, Dan‐Yun Ruan, Ziyong Xiang, Ina Nordman, Feng Wang, Jaspreet Singh Grewal, Ling Zhang, Pamela N. Münster, Yanhong Deng, Xiaoxi Xie, Jianzhen Shan, Yan Dong, Jingdong Zhang, Xiaohua Hu, Rui‐Hua Xu, Yihong Zhang, XingYa Li, Haoxiang Wu, Steven Hager, Keun Wook Lee, Shaozhong Wei, Xinfang Hou
article en
13 citations

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.

Signal Transduction and Targeted TherapyVol. 10(1)
Henry Ford Health System (US), Sun Yat-sen University (CN), Guangxi Medical University (CN), University of California, San Francisco (US), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Norton Healthcare (US), Providence Portland Medical Center (US), Sir Run Run Shaw Hospital (CN), Seoul National University Bundang Hospital (KR), Cabrini Hospital (AU), Fudan University Shanghai Cancer Center (CN), California Cancer Associates for Research and Excellence (US), Sixth Affiliated Hospital of Sun Yat-sen University (CN), Medical Center Hospital (US), Beijing Luhe Hospital Affiliated to Capital Medical University (CN), Albury Wodonga Health (AU), First Affiliated Hospital of GuangXi Medical University (CN), Henan Cancer Hospital (CN), Sun Yat-sen University Cancer Center (CN), Calvary Mater Newcastle Hospital (AU), Linear Clinical Research (AU), First Affiliated Hospital of Zhengzhou University (CN), The Catholic University of Korea Seoul St. Mary's Hospital (KR), Hubei Cancer Hospital (CN), Liaoning Cancer Hospital & Institute (CN), First Affiliated Hospital Zhejiang University (CN), Dong-A University (KR), Zhejiang University (CN)
Good health and well-being
Openalex Percentile: Top 1%
Colorectal Cancer Treatments and Studies
13.59
DOIOpen Access PDFOpenAlex
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