METHODS: A scoping review of clinical trial registries ( Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on PD-1/PD-L1 Inhibitors for early and middle-stage MSI-H and MSS CRC was done up to March 2024.
RESULTS: A total of 19 trials related to early to mid-stage MSH-I or MSS CRC were included. Among them, 6 trials are in recruiting status, 3 trials are in active, not recruiting status, 3 trials are completed, 1 trial is terminated, and 1 trial is unknown. Of these, 9 trials involve MSI-H type CRC, and 10 trials involve MSS type CRC. Preclinical phase I/II trials are predominant, with only 3 clinical phase III trials. In trials related to MSI-H type CRC, 4 studies involve PD-1/PD-L1 inhibitors combined with neoadjuvant therapy, and 5 studies involve combination therapy. In trials related to MSS type CRC, 3 studies involve PD-1/PD-L1 inhibitors combined with targeted therapy, 2 studies involve PD-1/PD-L1 inhibitors combined with chemotherapy, 1 study involves PD-1/PD-L1 inhibitor combined immunotherapy, 1 study involves PD-1/PD-L1 inhibitors combined with bacterial therapy, and 3 studies involve PD-1/PD-L1 inhibitors combined with comprehensive therapy. As for primary outcome measures, 4 trials select pathological complete response rates, 3 trials select progression-free survival rate, 3 trials select objective response rate, 3 trials select overall survival rate, 4 trials select disease-free survival rate, 1 trial selects clinical complete response rate, and 1 trial selects percentage of participants with a dose-limiting toxicity.
CONCLUSIONS: For early- and middle-stage MSI-H and MSS CRC, PD-1/PD-L1 inhibitors have shown some therapeutic efficacy, as evidenced by phase I/II studies. However, contemporary trial designs exhibit heterogeneity, with relatively few inclusion criteria, the use of various drug combinations and regimens, and significant variations in reported endpoints. Nevertheless, more double-arm, multicenter, randomized controlled trials are still needed to confirm the efficacy of immunotherapy.
方法:截至2024年3月,对临床试验注册(Clinicaltrials.gov和EU临床试验注册)和PubMed/Medline数据库中PD-1/PD-L1抑制剂早期和中期MSI-H和MSSCRC的临床试验进行了范围审查。
结果:共纳入19项与早期至中期MSH-I或MSSCRC相关的试验。其中,6项试验处于招募状态,3个试验正在进行中,不是招募状态,3个试验完成,1次审判终止,1个试验未知。其中,9项试验涉及MSI-H型CRC,10项试验涉及MSS类型CRC。临床前I/II期试验占主导地位,只有3个临床III期试验。在与MSI-H型CRC相关的试验中,4项研究涉及PD-1/PD-L1抑制剂联合新辅助治疗,5项研究涉及联合治疗。在与MSS类型CRC相关的试验中,3项研究涉及PD-1/PD-L1抑制剂联合靶向治疗,2项研究涉及PD-1/PD-L1抑制剂联合化疗,1项研究涉及PD-1/PD-L1抑制剂联合免疫治疗,1项研究涉及PD-1/PD-L1抑制剂联合细菌治疗,3项研究涉及PD-1/PD-L1抑制剂联合综合治疗。至于主要结果指标,4项试验选择病理完全缓解率,3项试验选择无进展生存率,3项试验选择客观反应率,3项试验选择总体生存率,4项试验选择无病生存率,1项试验选择临床完全缓解率,1项试验选择了具有剂量限制性毒性的参与者的百分比。
结论:对于早期和中期MSI-H和MSSCRC,PD-1/PD-L1抑制剂已显示出一定的治疗效果,I/II期研究证明了这一点。然而,当代试验设计表现出异质性,纳入标准相对较少,使用各种药物组合和方案,以及报告终点的显著差异。然而,更多的双臂,多中心,仍需要随机对照试验来证实免疫治疗的疗效.