程序性死亡受体-1抑制剂在碱基错配修复缺陷/微卫星高度不稳定型晚期结直肠癌中的研究进展

Advances in programmed death-1 inhibitors for advanced colorectal cancer with defective mismatch repair/microsatellite instability-high

目的了解程序性死亡受体-1(programmed death-1,PD-1)抑制剂在碱基错配修复缺陷(defective mismatch repair,dMMR)/微卫星高度不稳定(microsatellite instability-high,MSI-H)型晚期结直肠癌(colorectal cancer,CRC)中应用的效果。方法回顾近年来国内外关于PD-1抑制剂在dMMR/MSI-H型晚期CRC中的相关研究并进行归纳总结。结果目前有较多研究探索了抗PD-1抑制剂治疗dMMR/MSI-H型晚期CRC(包括局部进展期CRC和转移性CRC),仍有部分研究正在试验中。这些研究均发现,采用PD-1抑制剂作为dMMR/MSIH型晚期CRC的一线或后线以及新辅助治疗均呈现了较好的生存获益,尤其在合并BRAF/RAS突变的d MMR/MSI-H型转移性CRC和新辅助免疫治疗后期望器官保留的局部进展期dMMR/MSI-H型CRC中已初见成效;而且有较多研究进一步探索了“双免治疗”,多数研究发现其疗效优于单免治疗,但同时也发现“双免治疗”较单免治疗会有更多的不良事件报道。结论从综述的文献研究结果总体看,PD-1抑制剂在dMMR/MSI-H型晚期CRC中临床获益明显,然而仍有更多问题亟待进一步探讨,比如提供更多的PD-1抑制剂一线药物,克服耐药性及其不良事件。未来需在临床实践中通过更精确的个体化识别以及更高效的联合用药方案,让dMMR/MSI-H型晚期CRC患者进一步从中获益。

Objective To understand the effect of programmed death-1(PD-1)inhibitors on defective mismatch repair(dMMR)/microsatellite instability-high(MSI-H)advanced colorectal cancer(CRC).Method The literature of recent research relevant PD-1 inhibitors in the utility for patients with dMMR/MSI-H advanced CRC was reviewed and summarized.Results At present,there were many studies exploring the utility of anti-PD-1 inhibitors for the treatment of dMMR/MSI-H advanced CRC(including locally advanced CRC and metastatic CRC),and some studies were still in trials.Studies had consistently shown that the use of PD-1 inhibitors in dMMR/MSI-H advanced CRC as first-line or subsequent therapy,as well as in the neoadjuvant setting,leading to significant survival benefits.These benefits were particularly notable in cases of dMMR/MSI-H metastatic CRC with concurrent BRAF/RAS mutations and in the context of neoadjuvant immunotherapy aimed at organ preservation in locally advanced dMMR/MSI-H CRC.Moreover,there were numerous studies exploring“dual immunotherapy”,and most studies found that its efficacy was superior to that of single immunotherapy.However,the more adverse events were reported by the“dual immunotherapy”compared to the single immunotherapy.Conclusions Overall,based on results of the literature reviewed,PD-1 inhibitors have shown significant clinical benefits in dMMR/MSI-H advanced CRC,but there are still more issues that need to be further explored,such as discovering more first-line PD-1 inhibitors,overcoming drug resistance and adverse events.Future clinical practice should prioritize more precise individualized identification and the application of more effective combination therapy regimens to further optimize outcomes for patients with dMMR/MSI-H advanced CRC.