加西他滨，一种KRAS G12C抑制剂，联合或不联合西妥昔单抗（一种EGFR抗体），用于晚期实体瘤KRAS G12C突变的II期试验的结直肠癌队列。

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.

作者信息

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

机构信息

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.

Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.

出版信息

Signal Transduct Target Ther. 2025 Jun 17;10(1):189. doi: 10.1038/s41392-025-02274-z.

DOI:10.1038/s41392-025-02274-z

PMID:40523897

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12170901/

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.

摘要

长期以来，KRAS基因的突变一直被认为与结直肠癌（CRC）的发病机制有关。KRAS G12C抑制剂克服了“不可成药”的挑战，实现了精准治疗。加索拉西布（D-1553）是一种高效且选择性的KRAS G12C抑制剂，在早期临床试验中已显示出有前景的抗肿瘤活性和良好的安全性。我们开展了一项开放标签、非随机的II期试验（ClinicalTrials.gov，NCT04585035），以评估加索拉西布联合或不联合西妥昔单抗在KRAS G12C突变型CRC中的安全性和疗效。在单药治疗队列（n = 26）中，客观缓解率（ORR）为19.2%（95%CI，6.6 - 39.4），疾病控制率（DCR）为92.3%（95%CI，74.9 - 99.1），中位无进展生存期（PFS）为5.5个月（95%CI，2.9 - 11.6），中位总生存期（OS）为13.1个月（95%CI，9.5 - NE）。在联合治疗队列（n = 42）中，ORR为45.2%（95%CI，29.8 - 61.3），DCR为92.9%（95%CI，80.5 - 98.5），中位PFS为7.5个月（95%CI，5.5 - 8.1），中位OS未达到。单药治疗组和联合治疗组分别有5例（19.2%）和6例（14.3%）患者发生≥3级治疗相关不良事件。加索拉西布联合或不联合西妥昔单抗在KRAS G12C突变型CRC的重度预处理患者中显示出有前景的疗效和可控的安全性，为该人群提供了一种潜在的新治疗方法。