KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials

IF 5.5 2区医学 Q1 HEMATOLOGY

Critical reviews in oncology/hematology Pub Date : 2025-04-22 DOI:10.1016/j.critrevonc.2025.104741

Erman Akkus , Nejat Emre Öksüz , Enes Erul

{"title":"KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials","authors":"Erman Akkus , Nejat Emre Öksüz , Enes Erul","doi":"10.1016/j.critrevonc.2025.104741","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>1–2 % of metastatic colorectal cancers (mCRC) harbor an activating <em>KRAS-</em>G12C mutation<em>.</em> This study aims to pool the results of available clinical trials of <em>KRAS</em>-G12C inhibitors, comparing monotherapy and combinations.</div></div><div><h3>Methods</h3><div>A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a <em>KRAS-</em>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.</div></div><div><h3>Results</h3><div>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<sup>2</sup>: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3–27.3) (I<sup>2</sup>: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4–7.1) (I<sup>2</sup>: 80.8) vs. 4.2 months (95 %CI: 3.6–4.7) (I<sup>2</sup>: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<sup>2</sup>:42.5) vs.16.5 % (95 %CI: 4.9–33.1) (I<sup>2</sup>: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.</div></div><div><h3>Conclusion</h3><div>This analysis suggests that <em>KRAS-</em>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.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"211 ","pages":"Article 104741"},"PeriodicalIF":5.5000,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Critical reviews in oncology/hematology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1040842825001295","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

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.

Methods

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.

Results

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) (I²: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3–27.3) (I²: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4–7.1) (I²: 80.8) vs. 4.2 months (95 %CI: 3.6–4.7) (I²:0.0), 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) (I²:42.5) vs.16.5 % (95 %CI: 4.9–33.1) (I²: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

Conclusion

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.

查看原文本刊更多论文

KRAS G12C抑制剂单独或联合治疗转移性结直肠癌：来自I-II-III期试验的疗效和毒性的比例和比较荟萃分析

1 - 2 %的转移性结直肠癌（mCRC）含有激活KRAS-G12C突变。本研究旨在汇总KRAS-G12C抑制剂的现有临床试验结果，比较单药治疗和联合治疗。方法系统检索MEDLINE数据库和ESMO/ASCO会议摘要。包括研究KRAS-G12C抑制剂在mCRC患者中的I-II-III期试验。主要终点是客观缓解率（ORR）和无进展生存期（PFS）。采用随机效应模型对单药和联合治疗的合并比例和比较亚组进行分析。结果：在14个研究队列中，596例既往治疗过的mCRC患者接受了sotorasib、adagagasib、divarasib或olomorasib中的一种单独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) (I2: 87.1)，显著高于单药治疗[16.7 %,(95 %CI: 8.3-27.3) (I2: 73.2)] （p = 0.045）。联合治疗的中位PFS明显更长[5.7个月（95 %CI: 4.4-7.1）（I2: 80.8） vs. 4.2个月（95 %CI: 3.6-4.7）（I2:0.0）， p = 0.027]。3-4级治疗相关不良事件（TRAEs）明显高于联合用药[32.8% %(95 %CI: 26.4-39.6) (I2:42.5) vs. 16.5% %(95 %CI: 4.9-33.1) (I2: 84.2), p = 0.047]。联合用药常见的不良事件有皮肤毒性、甲沟炎和低镁血症。结论：该分析表明，KRAS-G12C抑制剂联合抗egfr药物与先前治疗过的mCRC患者相比，可能提供双倍的ORR和1.5个月的PFS获益，但具有双倍的3-4级TRAEs，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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Critical reviews in oncology/hematology 医学-血液学

CiteScore

11.00

自引率

3.20%

发文量

213

审稿时长

55 days

期刊介绍： Critical Reviews in Oncology/Hematology publishes scholarly, critical reviews in all fields of oncology and hematology written by experts from around the world. Critical Reviews in Oncology/Hematology is the Official Journal of the European School of Oncology (ESO) and the International Society of Liquid Biopsy.