在CAPRI-2 GOIM试验中，通过液体活检进行的综合基因组分析描绘了转移性结直肠癌的突变图谱，以预测FOLFIRI联合西妥昔单抗的抗肿瘤疗效。
Comprehensive genomic profiling by liquid biopsy portrays metastatic colorectal cancer mutational landscape to predict antitumor efficacy of FOLFIRI plus cetuximab in the CAPRI-2 GOIM trial.
作者信息
Ciardiello D, Boscolo Bielo L, Napolitano S, Latiano T P, De Stefano A, Tamburini E, Toma I, Bordonaro R, Russo A E, Pisconti S, Nisi C, Lotesoriere C, Vallarelli S, Lonardi S, Iacono D, Cremolini C, Tortora G, Tagliaferri P, Pietrantonio F, Rosati G, Lucenti A, Scartozzi M, Brunetti O, Cinieri S, Zampino M G, Zaniboni A, Berardi R, Paoletti G, Febbraro A, Martinelli E, Troiani T, Cioli E, Normanno N, Di Maio M, Parente P, Fazio N, Curigliano G, De Vita F, Avallone A, Maiello E, Ciardiello F, Martini G
机构信息
Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.
Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.
出版信息
ESMO Open. 2025 Apr;10(4):104511. doi: 10.1016/j.esmoop.2025.104511. Epub 2025 Mar 18.
BACKGROUND
Limited evidence is currently available on the role of liquid biopsy (LBx) in predicting the efficacy of anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (mCRC).
METHODS
The CAPRI-2 GOIM is a phase II trial investigating the use of LBx-comprehensive genomic profiling (CGP)-guided, cetuximab-based treatment through three subsequent lines of therapy in patients with RAS/BRAF wild-type (WT) mCRC. LBx-CGP is carried out at baseline and at progressive disease to first- and second-line therapies. In case of RAS/BRAF WT circulating tumor DNA at progressive disease, EGFR therapeutic blockade is continued by combining cetuximab with a different chemotherapy backbone. The primary endpoint is overall response rate (ORR) by RECIST 1.1 criteria. Tumor molecular characteristics by LBx-CGP are correlated with treatment efficacy.
RESULTS
One hundred and ninety-two RAS/BRAF WT microsatellite stable mCRC patients treated with FOLFIRI plus cetuximab with baseline LBx-CGP and assessable for response were included in the analysis. One hundred and thirty-seven patients with WT tumors for potential anti-EGFR drug resistance genes (RAS/BRAF/EGFR/PIK3CA/MAP2K1/MET/RET/ALK/ROS1/NTRK/NF1/FGFR, and HER2 amplification; 'negatively hyper-selected' cases) had 78.1% ORR compared with 54.5% ORR for patients with mutations [odds ratio 2.95, 95% confidence interval (CI) 1.44-6.10, P = 0.001]. 'Negatively hyper-selected' patients had median progression-free survival of 12.35 months (95% CI 10.58-15.4 months) compared with 8.68 months (95% CI 4.87-12.1 months) for patients with mutations (hazard ratio 0.64, 95% CI 0.44-0.92, P = 0.017). High cancer cell clonality of pathogenic variants (PVs) correlated with worse median progression-free survival (3.55 months, 95% CI 2.57 months to NE) compared with low cancer cell clonality of PV (9.63 months, 95% CI 7.16 months to NE, P = 0.21). After first-line therapy failure, approximately one out of five patients had acquired PVs of potential anti-EGFR drug resistance genes, whereas RAS/BRAF WT circulating tumor DNA was maintained in most patients (78.5%).
CONCLUSIONS
These results support the integration of LBx-CGP for implementing the efficacy and for optimizing the use of anti-EGFR therapies in RAS/BRAF WT mCRC.
背景
目前关于液体活检（LBx）在预测转移性结直肠癌（mCRC）中抗表皮生长因子受体（EGFR）治疗疗效方面的作用，证据有限。
方法
CAPRI-2 GOIM是一项II期试验，研究在RAS/BRAF野生型（WT）mCRC患者中，通过后续三线治疗使用基于LBx综合基因组分析（CGP）指导的、以西妥昔单抗为基础的治疗。LBx-CGP在基线以及一线和二线治疗疾病进展时进行。如果在疾病进展时RAS/BRAF WT循环肿瘤DNA存在，通过将西妥昔单抗与不同的化疗方案联合继续进行EGFR治疗阻断。主要终点是根据RECIST 1.1标准的总缓解率（ORR）。通过LBx-CGP获得的肿瘤分子特征与治疗疗效相关。
结果
分析纳入了192例接受FOLFIRI加西妥昔单抗治疗、有基线LBx-CGP且可评估反应的RAS/BRAF WT微卫星稳定mCRC患者。137例潜在抗EGFR耐药基因（RAS/BRAF/EGFR/PIK3CA/MAP2K1/MET/RET/ALK/ROS1/NTRK/NF1/FGFR和HER2扩增；“阴性超选择”病例）WT肿瘤患者的ORR为78.1%。相比之下，有突变的患者ORR为54.5%（优势比2.95，95%置信区间[CI]1.44 - 6.10，P = 0.001）。“阴性超选择”患者的无进展生存期（PFS）中位数为12.35个月（95%CI 10.58 - 15.4个月），而有突变的患者为8.68个月（95%CI 4.87 - 12.1个月）（风险比0.64，95%CI 0.44 - 0.92，P = 0.017）。与低癌细胞克隆性的致病变异（PV）相比，高癌细胞克隆性的PV与更差的PFS中位数相关（3.55个月，95%CI 2.57个月至未达到）（9.63个月，95%CI 7.16个月至未达到，P = 0.21）。一线治疗失败后，约五分之一的患者获得了潜在抗EGFR耐药基因的PV，而大多数患者（78.5%）仍维持RAS/BRAF WT循环肿瘤DNA。
结论
这些结果支持将LBx-CGP整合用于评估RAS/BRAF WT mCRC中抗EGFR治疗的疗效并优化其使用。
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