Table 2_The efficacy and safety of regorafenib/fruquintinib combined with PD-1/PD-L1 for metastatic colorectal cancer: a meta-analysis based on single-arm studies.docx

ObjectiveThe efficacy of regorafenib or fruquintinib in combination with PD-1/PD-L1 inhibitors for metastatic colorectal cancer (mCRC) treatment has not been elucidated. This study aims to systematically evaluate the efficacy and safety of this combination therapy.
MethodsPubMed, Embase, Cochrane Library, and Web of Science were systematically retrieved until July 24, 2024. A meta-analysis was carried out for the overall objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and the incidence of grade 3 or higher treatment-related adverse events (AEs). Non-overlapping 95% confidence intervals (CIs) were considered statistically significant.
Results26 studies encompassing 1,409 patients were analyzed. Pooled analysis revealed an ORR of 6% (95% CI: 3%-12%), a DCR of 62% (95% CI: 55%-68%), a median PFS of 3.84 months (95% CI: 3.19-4.49 months), a median OS of 13.08 months (95% CI: 10.17-16.00 months), and an incidence rate of grade 3–4 AEs of 21% (95% CI: 15%-28%). In subgroup analyses, the fruquintinib-based regimen demonstrated significantly superior efficacy compared to regorafenib-based therapy, with higher ORR (16% [95% CI: 13%-21%] vs 3% [95% CI: 1%-9%]), DCR (79% [95% CI: 72%-85%] vs 54% [95% CI: 47%-61%]), and median PFS (5.40 months [95% CI: 4.60-6.19] vs 3.00 months [95% CI: 2.47-3.52]). Median OS was numerically but not significantly longer with fruquintinib (14.35 months [95% CI: 10.68-18.02] vs 12.70 months [95% CI: 8.79-16.61]). Liver metastasis status strongly influenced outcomes, with significantly lower ORR (3% [95% CI: 1%-13%] vs 49% [95% CI: 32%-76%]) and shorter median PFS (2.37 months [95% CI: 1.77-2.96] vs 3.50 months [95% CI: 3.09-3.91]) in patients with liver involvement.
ConclusionThe combination of regorafenib or fruquintinib with PD-1/PD-L1 shows moderate efficacy and acceptable safety in the treatment of mCRC. The fruquintinib-based regimen may be superior to the regorafenib-based regimen, and patients without liver metastasis may derive greater benefits. These findings offer new insights for treating mCRC, although they should be validated through large randomized controlled trials.
Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO, identifier CRD42024582268

目的：瑞戈非尼（regorafenib）或呋喹替尼（fruquintinib）联合程序性死亡受体1（programmed cell death protein 1, PD-1）/程序性死亡受体配体1（programmed death-ligand 1, PD-L1）抑制剂治疗转移性结直肠癌（metastatic colorectal cancer, mCRC）的疗效尚未阐明。本研究旨在系统评估该联合疗法的有效性与安全性。
方法：系统检索PubMed、Embase、Cochrane图书馆及Web of Science数据库，检索时限截至2024年7月24日。针对总体客观缓解率（objective response rate, ORR）、疾病控制率（disease control rate, DCR）、无进展生存期（progression-free survival, PFS）、总生存期（overall survival, OS）以及3级及以上治疗相关不良事件（adverse events, AEs）的发生率进行荟萃分析。以非重叠的95%置信区间（confidence interval, CI）作为统计学显著性判定依据。
结果：共纳入26项研究，涉及1409例患者。合并分析结果显示，总体客观缓解率为6%（95% CI：3%~12%），疾病控制率为62%（95% CI：55%~68%），中位无进展生存期为3.84个月（95% CI：3.19~4.49个月），中位总生存期为13.08个月（95% CI：10.17~16.00个月），3~4级治疗相关不良事件发生率为21%（95% CI：15%~28%）。亚组分析结果显示，基于呋喹替尼的联合方案疗效显著优于基于瑞戈非尼的治疗方案：客观缓解率分别为16%（95% CI：13%~21%）与3%（95% CI：1%~9%），疾病控制率分别为79%（95% CI：72%~85%）与54%（95% CI：47%~61%），中位无进展生存期分别为5.40个月（95% CI：4.60~6.19个月）与3.00个月（95% CI：2.47~3.52个月）。基于呋喹替尼方案的中位总生存期数值上更长，但未达到统计学显著性差异（14.35个月[95% CI：10.68~18.02个月] vs 12.70个月[95% CI：8.79~16.61个月]）。肝转移状态对治疗结局影响显著：伴肝转移患者的客观缓解率显著更低（3%[95% CI：1%~13%] vs 49%[95% CI：32%~76%]），中位无进展生存期也更短（2.37个月[95% CI：1.77~2.96个月] vs 3.50个月[95% CI：3.09~3.91个月]）。
结论：瑞戈非尼或呋喹替尼联合PD-1/PD-L1抑制剂治疗mCRC的疗效中等，安全性可接受。基于呋喹替尼的联合方案可能优于基于瑞戈非尼的方案，无肝转移患者可能获益更显著。本研究结果为mCRC的治疗提供了新的思路，但仍需通过大型随机对照试验加以验证。
系统评价注册信息：https://www.crd.york.ac.uk/PROSPERO，注册号为CRD42024582268