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| KRAS G12C靶向治疗的临床挑战与联合治疗策略 |
| Clinical Challenges and Combination Strategies in KRAS G12C-Targeted Therapy |
| 投稿时间：2026-10-15 修订日期：2026-10-15 |
| DOI： |
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| 中文关键词: KRAS G12C 黏着斑激酶 联合治疗 Ifebemtinib 非小细胞肺癌 结直肠癌 |
| 英文关键词:KRAS G12C focal adhesion kinase combination therapy Ifebemtinib non-small-cell lung cancer colorectal cancer |
| 基金项目:浙江省“尖兵领雁+X”科技计划项目(2025SDXT002-2 和2026C02A1108) |
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| 中文摘要: |
| KRAS G12C抑制剂为晚期肿瘤患者提供了新的治疗选择，但疗效持续性及长期耐受性仍需改善。针对治疗后的信号补偿和微环境支持开展联合，是进一步优化治疗的重要方向。黏着斑激酶（FAK）连接细胞黏附、生存信号与基质反应，为双靶联合提供了依据。笔者团队开展的ifebemtinib联合格索雷塞Ⅰb/Ⅱ期研究中，肺癌一线单臂队列纳入33例患者，确认客观缓解率为81.8%，中位起效时间为1.4个月，中位无进展生存期为22.3个月，3～4级治疗相关不良事件发生率为24.2%。经治结直肠癌随机研究中，联合组与格索雷塞单药组的确认客观缓解率为38.9%和16.7%，差异未达统计学显著性，中位无进展生存期为7.7个月和4.0个月。本文结合团队研究，讨论KRAS G12C治疗的临床挑战、主要联合策略及全口服去化疗方案的一线开发前景。 |
| 英文摘要: |
| KRAS G12C inhibitors have provided new treatment options for patients with advanced cancer. However, treatment responses may not last, and long-term tolerability remains a challenge. Combining these drugs with other treatments may help reduce compensatory signaling and support from the tumor microenvironment, which may improve treatment outcomes. Focal adhesion kinase (FAK) is involved in cell adhesion, cell survival signaling, and changes in the surrounding tissue. These functions provide a basis for combining FAK inhibitors with KRAS G12C inhibitors.
Our team studied ifebemtinib plus garsorasib in a phase 1b/2 trial. The trial included a single-arm cohort of 33 patients who received the combination as first-line treatment for non-small cell lung cancer (NSCLC). The confirmed objective response rate was 81.8%. The median time to response was 1.4 months, and the median progression-free survival was 22.3 months. Grade 3 or 4 treatment-related adverse events occurred in 24.2% of patients.
The trial also included a randomized cohort of patients with previously treated colorectal cancer. The confirmed objective response rate was 38.9% with the combination and 16.7% with garsorasib alone. This difference was not statistically significant. The median progression-free survival was 7.7 months with the combination and 4.0 months with garsorasib alone.
This commentary reviews the clinical challenges of KRAS G12C targeted therapy and current combination strategies. It also discusses our team''s findings and the potential of a fully oral regimen without chemotherapy as a first-line treatment option. |
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