免疫检查点抑制剂治疗转移性结直肠癌的早期循环肿瘤DNA与生存情况：SAMCO-PRODIGE 54随机临床试验的二次分析

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

作者信息

Taïeb Julien, Sullo Francesco Giulio, Lecanu Aurélie, Bourreau Camille, Barbier Emilie, Gandini Annalice, Bez Jérémie, Mulot Claire, Di Fiore Frederic, Elhajbi Farid, Borg Christophe, Bouché Olivier, Aparicio Thomas, Zaanan Aziz, André Thierry, Tougeron David, Taly Valerie, Laurent-Puig Pierre

机构信息

Service de gastroenterologie et d'oncologie digestive, Paris CARPEM (Cancer research for personalized medicine) institute, Hopital Européen Georges Pompidou, Assistance Publique Hopitaux de Paris (AP-HP), Université Paris Cité, Paris, France.

Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Université Paris Cité, Sorbonne Université, Equipe labellisée Ligue Nationale Contre le Cancer, Paris, France.

出版信息

JAMA Oncol. 2025 Jun 18. doi: 10.1001/jamaoncol.2025.1646.

DOI:10.1001/jamaoncol.2025.1646

PMID:40531517

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12177728/

Abstract

IMPORTANCE

Immune checkpoint inhibitors (ICIs) have dramatically transformed the therapeutic landscape of deficient mismatch repair/microsatellite unstable-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC); however, ICI use is challenged by primary resistance and timing of discontinuation. Whether circulating tumor DNA (ctDNA) may be predictive of progression-free survival (PFS) and overall survival (OS) in this treatment context remains unknown.

OBJECTIVE

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.

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

INTERVENTION

Avelumab or standard chemotherapy with or without targeted agents.

MAIN OUTCOMES AND MEASURES

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

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

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.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT03186326.

摘要

重要性

免疫检查点抑制剂（ICI）显著改变了错配修复缺陷/微卫星高度不稳定（dMMR/MSI-H）转移性结直肠癌（mCRC）的治疗格局；然而，ICI的使用面临着原发性耐药和停药时机的挑战。在这种治疗背景下，循环肿瘤DNA（ctDNA）是否可预测无进展生存期（PFS）和总生存期（OS）仍不清楚。

目的

评估通过肿瘤特异性甲基化标志物检测的ctDNA在接受ICI治疗的dMMR/MSI-H mCRC患者中的预后和预测作用。

设计、设置和参与者：这项对SAMCO-PRODIGE 54随机临床试验的预先指定的二次分析评估了接受阿维鲁单抗或标准化疗（二线治疗中有无靶向药物）的dMMR/MSI-H mCRC患者的ctDNA，以评估其预后作用。前瞻性获取血浆样本用于ctDNA分析，并使用针对WIF1和NPY基因的亚硫酸氢盐转化的游离DNA（cfDNA）的数字液滴聚合酶链反应扩增来定量ctDNA水平。这些样本于2018年4月至2021年4月在法国的49个地点收集，分别在基线时（V1）和治疗开始后1个月（V2）采集。数据分析于2024年10月1日至11月1日进行。

干预措施

阿维鲁单抗或含或不含靶向药物的标准化疗。

主要结局和测量指标

根据基线ctDNA阳性或浓度以及早期ctDNA变化（ΔctDNA = [V1 - V2]÷V1）得出的PFS和OS。

结果

预测分析纳入了99例患者（平均[标准差]年龄为66[13]岁；51例女性[51.5%]），这些患者在V1时有可用于ctDNA评估的血浆样本，其中74例在V2时也有样本可用于ctDNA变化评估。在99例有V1血浆样本的患者中，基线ctDNA阳性或浓度与临床结局无关。ctDNA变化（以中位数为临界值）与PFS（风险比[HR]，2.98；95%置信区间，1.77 - 5.01；P <.001）和OS（HR，3.61；95%置信区间，1.81 - 7.17；P <.001）均显著相关。这种关联在接受阿维鲁单抗治疗的患者中比接受化疗的患者更明显（PFS HR，4.22；95%置信区间，1.77 - 10.1；P =.001；OS HR，17.40；95%置信区间，3.82 - 79.70；P <.001）（化疗组PFS HR，2.09；95%置信区间，1.03 - 4.21；P =.04；OS HR，1.51；95%置信区间，0.61 - 3.72；P =.38）。阿维鲁单抗（与化疗相比）在ctDNA反应良好的患者中改善了PFS（HR，0.33；95%置信区间，0.14 - 0.77；对数秩P =.008），但在反应不佳的患者中未改善（HR，1.32；95%置信区间，0.67 - 2.62；对数秩P =.42）。联合ctDNA反应和实体瘤疗效评价标准（RECIST）1.1版评估可准确预测长期OS。在多变量分析中，ctDNA无反应与阿维鲁单抗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），但在化疗组中无此关联（HR，1.61；95%置信区间，0.66 - 3.93；P =.30）。