Akkus Erman, Öksüz Nejat Emre, Erul Enes
Ankara University Faculty of Medicine, Department of Medical Oncology, Ankara, Türkiye; Ankara University Cancer Research Institute, Ankara, Türkiye.
Ankara University Faculty of Medicine, Department of Medical Oncology, Ankara, Türkiye; Ankara University Cancer Research Institute, Ankara, Türkiye.
Crit Rev Oncol Hematol. 2025 Jul;211:104741. doi: 10.1016/j.critrevonc.2025.104741. Epub 2025 Apr 22.
1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.
A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.
596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.
This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.
1%-2%的转移性结直肠癌（mCRC）存在KRAS-G12C激活突变。本研究旨在汇总KRAS-G12C抑制剂现有临床试验的结果，比较单药治疗和联合治疗。
在MEDLINE数据库和ESMO/ASCO会议摘要中进行系统的文献检索。纳入在mCRC患者中研究KRAS-G12C抑制剂的I-II-III期试验。主要终点为客观缓解率（ORR）和无进展生存期（PFS）。采用随机效应模型呈现单药治疗和联合治疗的合并比例及比较亚组分析结果。
纳入了14个研究队列中的596例既往接受过治疗的mCRC患者，这些患者接受了索托拉西布、阿达格拉西布、迪瓦拉西布或奥洛莫拉西布中的一种作为单药治疗或与西妥昔单抗/帕尼单抗联合治疗。联合治疗的ORR为33.9%（95%CI：20.7-48.4）（I：87.1），显著高于单药治疗[16.7%，（95%CI：8.3-27.3）（I：73.2）]（p = 0.045）。联合治疗的中位PFS显著更长[5.7个月（95%CI：4.4-7.1）（I：80.8） vs. 4.2个月（95%CI：3.6-4.7）（I：0.0），p = 0.027]。联合治疗的3-4级治疗相关不良事件（TRAEs）显著更常见[32.8%（95%CI：26.4-39.6）（I：42.5） vs. 16.5%（95%CI：4.9-33.1）（I：84.2），p = 0.047]。联合治疗特有的常见不良事件为皮肤毒性、甲沟炎和低镁血症。
该分析表明，在既往接受过治疗的mCRC患者中，KRAS-G12C抑制剂与抗EGFR药物联合使用相比单药治疗可能使ORR翻倍，PFS延长1.5个月，但3-4级TRAEs增加一倍，包括皮肤毒性、甲沟炎和低镁血症。在这些高度预处理的患者中，治疗选择应个体化。
