Early ctDNA and Survival in Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors: A Secondary Analysis of the SAMCO-PRODIGE 54 Randomized Clinical Trial.

Whether circulating tumor DNA (ctDNA) may be predictive of progression-free survival(PFS) and overall survival(OS) in this treatment context remains unknown.

在这种治疗背景下，循环肿瘤DNA（ctDNA）是否可以预测无进展生存（PFS）和总生存（OS）仍然未知。

Background

To assess the prognostic and predictive role of ctDNA, detected by tumor-specific methylation markers, in patients with dMMR/MSI-H mCRC treated with ICIs.

评估通过肿瘤特异性甲基化标记物检测的循环肿瘤DNA（ctDNA）在使用免疫检查点抑制剂（ICIs）治疗的错配修复缺陷（dMMR）/微卫星不稳定性高（MSI-H）转移性结直肠癌（mCRC）患者中的预后和预测作用。

DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary analysis of the SAMCO-PRODIGE 54 randomized clinical trial evaluated ctDNA in patients with dMMR/MSI-H mCRC treated with avelumab or standard chemotherapy, with or without a targeted agent in the second-line setting, to assess its prognostic role.

设计、环境和参与者：这是SAMCO-PRODIGE 54随机临床试验的预定次要分析，评估了接受avelumab或标准化疗治疗的dMMR/MSI-H mCRC患者中的ctDNA，这些患者在二线治疗中可能使用或不使用靶向药物，以评估其预后作用。

Plasma samples were obtained prospectively for ctDNA analysis, and digital droplet polymerase chain reaction amplification of bisulfite-converted cell-free DNA (cfDNA) for WIF1 and NPY genes was used to quantify ctDNA levels.

前瞻性地获取血浆样本以进行循环肿瘤DNA（ctDNA）分析，使用数字滴定聚合酶链反应扩增双硫仑转化的无细胞DNA（cfDNA）的WIF1和NPY基因，以量化ctDNA水平。

These samples were collected from April 2018 to April 2021 at 49 sites in France at baseline (V1) and 1-month posttreatment initiation (V2) during.

这些样本是在2018年4月至2021年4月期间，在法国的49个地点在基线（V1）和治疗开始后1个月（V2）期间收集的。

Data analyses were performed from October 1 to November 1, 2024.

数据分析工作从2024年10月1日持续到11月1日。

intervention

Avelumab or standard chemotherapy with or without targeted agents.

接受avelumab治疗或标准化疗，可选择性地联合或不联合靶向药物。

main_outcomes_and_measures

PFS and OS according to baseline ctDNA positivity or concentration, and early ctDNA variation (ΔctDNA = [V1-V2] ÷ V1).

根据基线 ctDNA 阳性或浓度以及早期 ctDNA 变化（ΔctDNA = [V1-V2] ÷ V1）来评估无进展生存期（PFS）和总生存期（OS）。

Results

The predictive analysis included 99 patients (mean [SD] age, 66 [13] years; 51 female [51.5%]) with plasma samples available for ctDNA assessment at V1, of which 74 had samples available also at V2 for Change in ctDNA assessment.

预测分析包括99名患者（平均年龄[标准差]为66[13]岁；51名女性[51.5%]），他们在V1时有可用于ctDNA评估的血浆样本，其中74名患者在V2时也有样本可用于ctDNA变化评估。

In the 99 patients with available V1 plasma samples, baseline ctDNA positivity or concentration were not associated with clinical outcomes.

在99名有可用V1血浆样本的患者中，基线循环肿瘤DNA（ctDNA）阳性或浓度与临床结果无关。

Change in ctDNA (cutoff at median value) was significantly associated with both PFS (hazard ratio[HR], 2.98; 95% CI, 1.77-5.01; P < .001) and OS (HR, 3.61; 95% CI, 1.81-7.17; P < .001).

循环肿瘤DNA（ctDNA）的变化（以中位数为截断值）与无进展生存期（PFS）显著相关（风险比[HR]，2.98；95%置信区间，1.77-5.01；P < .001）以及总生存期（OS）（HR，3.61；95%置信区间，1.81-7.17；P < .001）。

This association was evident in patients treated with avelumab (PFS HR, 4.22; 95% CI, 1.77-10.1; P = .001; OS HR, 17.40; 95% CI, 3.82-79.70; P < .001) than in those receiving chemotherapy (PFS HR, 2.09; 95% CI, 1.03-4.21; P = .04; OS HR, 1.51; 95% CI, 0.61-3.72; P = .38).

这种关联在使用avelumab治疗的患者中表现明显（无进展生存期（PFS）风险比（HR），4.22；95%置信区间（CI），1.77-10.1；P = .001；总生存（OS）HR，17.40；95% CI，3.82-79.70；P < .001），而在接受化疗的患者中则不那么明显（PFS HR，2.09；95% CI，1.03-4.21；P = .04；OS HR，1.51；95% CI，0.61-3.72；P = .38）。

Avelumab (vs chemotherapy) improved PFS in favorable ctDNA responders (HR, 0.33; 95% CI, 0.14-0.77; log-rank P = .008) but not in poor responders (HR, 1.32; 95% CI, 0.67-2.62; log-rank P = .42) Combined ctDNA response and RECIST, version 1.1, assessment accurately predicted long-term OS.

与化疗相比，avelumab改善了ctDNA反应良好的患者的无进展生存期（PFS）（HR，0.33；95% CI，0.14-0.77；log-rank P = .008），但在反应不良的患者中则没有（HR，1.32；95% CI，0.67-2.62；log-rank P = .42）。ctDNA反应和RECIST，第1.1版评估的结合准确预测了长期总生存（OS）。

In the multivariable analysis, lack of ctDNA response was associated with an increased risk of disease progression and death in the avelumab group (HR, 7.27; 95% CI, 2.23-23.7; P = .001) but not in the chemotherapy group (HR, 1.61; 95% CI, 0.66-3.93; P = .30).

在多变量分析中，ctDNA无反应与avelumab组疾病进展和死亡风险增加相关（HR，7.27；95% 置信区间，2.23-23.7；P = .001），但在化疗组中则没有这种相关性（HR，1.61；95% 置信区间，0.66-3.93；P = .30）。

Conclusions

The findings of this secondary analysis of an RCT found that change in ctDNA at 1-month posttreatment can predict long-term outcomes in patients with dMMR/MSI-H mCRC treated with ICIs.

这项随机对照试验的次要分析发现，在接受ICI治疗的dMMR/MSI-H mCRC患者中，治疗后1个月ctDNA的变化可以预测长期结果。

trial_registration

ClinicalTrials.gov Identifier: NCT03186326.

临床试验注册号：NCT03186326。