[评论]PD-1抗体、组蛋白去乙酰化酶抑制剂和VEGF抗体在微卫星稳定/错配修复正常型结直肠癌中的联合应用:一项随机2期试验
Combined anti-PD-1,HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer:a randomized phase 2 trial
WANG F JIN Y WANG M 张楠1
作者信息
- 1. 中国医科大学附属盛京医院消化道肿瘤科 辽宁沈阳 110000
- 折叠
摘要
包括组蛋白乙酰化在内的染色质表观遗传修饰和肿瘤血管生成在建立免疫抑制性肿瘤微环境中起关键作用.我们在这项随机2期试验——CAPability-01中,探讨程序性细胞死亡蛋白-1(programmed cell death protein-1,PD-1)单克隆抗体信迪利单抗+组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)西达本胺联合或不联合抗血管内皮生长因子(vascu-lar endothelial growth factor,VEGF)单克隆抗体贝伐珠单抗治疗不可切除的化疗难治性局部晚期或转移性微卫星稳定(micro-satellite stable,MSS)/错配修复正常(proficient mismatch repair,pMMR)型结直肠癌患者的潜在效能.本试验共有48例患者被随机分配至双药组(信迪利单抗+西达本胺,n=23)或三药组(信迪利单抗+西达本胺+贝伐珠单抗,n=25).结果显示,主要研究终点已达到——总体研究对象的第18周的无进展生存(progression-free survival,PFS)率(18wPFS率)为43.8%(21/48).次要研究终点的结果包括中位PFS期达3.7个月,总缓解率为29.2%(14/48),疾病控制率为56.3%(27/48),中位持续缓解时间达12.0个月,中位总生存时间数据尚不充分.与双药组相比,三药组的结果更优:18wPFS率更高(64.0%vs.21.7%,P=0.003),总缓解率更高(44.0%vs.13.0%,P=0.027)和中位PFS期更长(7.3个月 vs.1.5个月,P=0.006).在三药组和双药组中观察到最常见的与治疗相关的不良事件包括蛋白尿、血小板减少、中性粒细胞减少、贫血、白细胞减少和腹泻.共有2例与治疗相关的死亡病例(肝功能衰竭和肺炎).来自患者的bulk RNA测序数据分析结果表明,三药组合增强了CD8+T细胞浸润,诱导建立更具免疫活性的肿瘤微环境.我们的研究结果表明,联合应用PD-1抗体、HDACi和VEGF抗体是一种有前景的治疗MSS/pMMR型晚期结直肠癌患者的方案.ClinicalTrials.gov注册号:NCT04724239.
Abstract
Epigenetic modifications of chromatin,including histone acetylation,and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment.In the randomized phase 2 CAPability-01 trial,we investi-gated the potential efficacy of combining the programmed cell death protein-1(PD-1)monoclonal antibody sintilimab with the histone deacetylase inhibitor(HDACi)chidamide with or without the anti-vascular endothelial growth factor(VEGF)monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or meta-static microsatellite stable/proficient mismatch repair(MSS/pMMR)colorectal cancer.Forty-eight patients were randomly assigned to either the doublet arm(sintilimab and chidamide,n=23)or the triplet arm(sintilimab,chidamide and beva-cizumab,n=25).The primary endpoint of progression-free survival(PFS)rate at 18 weeks(18wPFS rate)was met with a rate of 43.8%(21 of 48)for the entire study population.Secondary endpoint results include a median PFS of 3.7 months,an overall response rate of 29.2%(14 of 48),a disease control rate of 56.3%(27 of 48)and a median duration of response of 12.0 months.The secondary endpoint of median overall survival time was not mature.The triplet arm ex-hibited significantly improved outcomes compared to the doublet arm,with a greater 18wPFS rate(64.0%versus 21.7%,P=0.003),higher overall response rate(44.0%versus 13.0%,P=0.027)and longer median PFS rate(7.3 months versus 1.5 months,P=0.006).The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria,thrombocytopenia,neutropenia,anemia,leukopenia and diarrhea.There were two treatment-related fatalities(hepatic failure and pneumonitis).Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+T cell infiltration,resulting in a more immunologically active tumor microenvi-ronment.Our study suggests that the combination of a PD-1 antibody,an HDACi,and a VEGF antibody could be a prom-ising treatment regimen for patients with MSS/pMMR advanced colorectal cancer.ClinicalTrials.gov registration:NCT04724239.
关键词
微卫星稳定/错配修复正常型结直肠癌/CAPability-01试验/信迪利单抗/西达本胺/贝伐珠单抗Key words
microsatellite stable/proficient mismatch repair colorectal cancer/CAPability-01 trial/sintilimab/chidamide/be-vacizumab引用本文复制引用
出版年
2024
国家科技期刊平台
NSTL
万方数据