免疫检查点抑制剂在二线或后线治疗微卫星不稳定型转移性结直肠癌中的疗效：一项使用合成对照臂的非随机评估。

Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation.

机构信息

Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France.

Statistical Unit, ARCAD Foundation, Paris, France.

出版信息

Eur J Cancer. 2024 Mar;199:113537. doi: 10.1016/j.ejca.2024.113537. Epub 2024 Jan 15.

DOI:10.1016/j.ejca.2024.113537

PMID:38241818

Abstract

PURPOSE

Immune checkpoint inhibitors (ICIs) appeared active in single-arm trials for patients with chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI). Given the paucity of randomised controlled trials (RCTs) in this setting, we evaluated the effect size of ICIs using intra-patients comparison and ARCAD database as historical controls.

PATIENTS AND METHODS

Individual-patient data from NIPICOL and CheckMate 142 phase II trials that evaluated a combination of ICIs for MSI mCRC patients (N = 176) and from five non-ICI mCRC historical RCTs in second-line or latter (N = 4026) were analyzed. Firstly, promising of ICIs was identified using intra-patient comparison based on growth modulation index (GMI) defined the ratio of progression-free survivals (PFS) on ICIs and previous line of therapy. Survival outcomes of ICIs-treated patients were then compared with those matched non-ICIs treated from ARCAD database historical RCTs.

RESULTS

Among ICIs-treated patients, median PFS on ICIs was 32.66 (range 0.10-74.25) versus 4.07 months (range 0.7-49.87) on prior therapy, resulting on median GMI of 4.97 (range 0.07-59.51; hazard-ratio (HR)= 0.16 (95 %CI=0.11-0.22, P < 0.001)). Compared to matched non-ICI patients, in third-line, median overall survival (OS) was not reached with ICIs versus 3.52 months with placebo (HR=0.20, 95 %CI=0.10-0.41, P < 0.001), and 6.51 months with active drugs (HR=0.30, 95 %CI=0.15-0.60, P = 0.001). In second-line, median OS was not reached with ICIs versus 11.7 months with chemotherapy+placebo (HR=0.12, 95 %CI=0.07-0.22, P < 0.001), and 16.3 months with chemotherapy+targeted therapy (HR=0.10, 95 %CI=0.05-0.19, P < 0.001).

CONCLUSION

ICIs demonstrates high effect size for MSI mCRC patients in second-line and later. This work might be useful as an example of methodology to avoid RCTs when benefit from experimental therapy is likely to be high.

摘要

目的

免疫检查点抑制剂（ICIs）在携带微卫星不稳定（MSI）的化疗耐药转移性结直肠癌（mCRC）患者的单臂试验中表现出活性。鉴于该环境中随机对照试验（RCT）的稀缺性，我们使用患者内比较和 ARCAD 数据库作为历史对照来评估 ICI 的效应大小。

患者和方法

分析了 NIPICOL 和 CheckMate 142 二期试验中评估 MSI mCRC 患者ICI 联合治疗的个体患者数据（N=176），以及来自五个非 ICI mCRC 二线或更晚期历史 RCT 的数据（N=4026）。首先，基于进展无进展生存（PFS）比（ICIs 和先前治疗线的 PFS 比值）定义的生长调节指数（GMI），使用患者内比较来确定 ICI 的疗效。然后将接受 ICI 治疗的患者的生存结果与来自 ARCAD 数据库历史 RCT 的匹配非 ICI 治疗患者进行比较。

结果

在接受 ICI 治疗的患者中，ICIs 治疗的中位 PFS 为 32.66 个月（范围 0.10-74.25），而先前治疗的中位 PFS 为 4.07 个月（范围 0.7-49.87），中位 GMI 为 4.97（范围 0.07-59.51；风险比（HR）=0.16（95%CI=0.11-0.22，P<0.001））。与匹配的非 ICI 患者相比，在三线治疗中，ICIs 组的中位总生存期（OS）未达到，而安慰剂组为 3.52 个月（HR=0.20，95%CI=0.10-0.41，P<0.001），而活性药物组为 6.51 个月（HR=0.30，95%CI=0.15-0.60，P=0.001）。在二线治疗中，ICIs 组的中位 OS 未达到，而化疗+安慰剂组为 11.7 个月（HR=0.12，95%CI=0.07-0.22，P<0.001），化疗+靶向治疗组为 16.3 个月（HR=0.10，95%CI=0.05-0.19，P<0.001）。