Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer
Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer
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DOI：
10.1200/jco.20.01225
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发表时间：
2020-10-01
影响因子：
45.3
通讯作者：
Di Maio, Massimo
中科院分区：
文献类型：
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作者：
Cremolini, Chiara;Antoniotti, Carlotta;Di Maio, Massimo
正确估计输注氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康的总生存期（OS）获益幅度缺乏FOLFOXIRI+贝伐珠单抗与双药+贝伐珠单抗的比较，因为所有研究该方案的试验都有OS以外的主要终点。为了以更高的把握度检验OS并探索治疗效果与主要患者和疾病特征的相互作用，我们进行了一项个体患者数据（IPD）荟萃分析。收集了5项合格试验的患者和方法：CHARTA（ClinicalTrials.gov标识符：NCT 01321957），OLIVIA（ClinicalTrials.gov标识符：NCT 00778102），STEAM（ClinicalTrials.gov标识符：NCT 01765582）、TRIBE（ClinicalTrials.gov标识符：NCT 00719797）和TRIBE 2（ClinicalTrials.gov标识符：NCT 02339116）。主要终点为OS。次要终点为无进展生存期（PFS）、客观缓解率（ORR）、R 0切除率、3/4级不良事件以及根据临床和分子特征进行的亚组分析。共有1，697例患者随机分配至FOLFOXIRI +贝伐单抗组（n = 846）或双联治疗+贝伐单抗组（n = 851）。大多数（78%）的东部肿瘤协作组体能状态为0，中位年龄为61岁。中位随访39.9个月后，分配至FOLFOXIRI +贝伐珠单抗组的患者的OS显著长于分配至双药治疗+贝伐珠单抗组的患者（中位数，28.9 vs 24.5个月;风险比[HR]，0.81; 95%CI，0.72 - 0.91; P < .001），试验间无显著异质性（P = 0.39; I-2 = 2%）。治疗组和研究特征之间未显示出显著的相互作用效应。分配至FOLFOXIRI +贝伐珠单抗组的患者PFS更长（中位数，12.2 vs 9.9个月; HR，0.74; 95% CI，0.67 - 0.82; P < .001），ORR较高（64.5% vs 53.6%; P < .001），R 0切除率较高（16.4%对11.8%; P = .007），3/4级中性粒细胞减少症的发生率较高（45.8%对21.5%; P < .001），发热性中性粒细胞减少症（6.3% v3.7%; P = 0.019）和腹泻（17.8%对8.4%; P < .001）。结论：与双联体+贝伐单抗相比，贝伐单抗显著且有意义地改善了转移性结直肠癌患者的生存期，并在PFS、ORR而R 0切除率的代价是毒性的中度增加。在BRAF突变型肿瘤患者中未观察到获益增加。
PURPOSEA proper estimation of the magnitude of the overall survival (OS) benefit from infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab versus doublets + bevacizumab is lacking because all trials that have investigated this regimen had primary end points other than OS. To test OS with higher power and to explore the interaction of treatment effect with main patient and disease characteristics, we performed an individual patient data (IPD) meta-analysis.PATIENTS AND METHODSIPD from 5 eligible trials were collected: CHARTA (ClinicalTrials.gov identifier: NCT01321957), OLIVIA (ClinicalTrials.gov identifier: NCT00778102), STEAM (ClinicalTrials.gov identifier: NCT01765582), TRIBE (ClinicalTrials.gov identifier: NCT00719797), and TRIBE2 (ClinicalTrials.gov identifier: NCT02339116). The primary end point was OS. Secondary end points were progression-free survival (PFS), objective response rate (ORR), R0 resection rate, grade 3/4 adverse events, and subgroup analyses according to clinical and molecular characteristics.RESULTSA total of 1,697 patients were randomly assigned to FOLFOXIRI + bevacizumab (n = 846) or doublets + bevacizumab (n = 851). Most (78%) had an Eastern Cooperative Oncology Group performance status of 0, and the median age was 61 years. After a median follow-up of 39.9 months, patients assigned to FOLFOXIRI + bevacizumab had significantly longer OS than those assigned to doublets + bevacizumab (median, 28.9 v 24.5 months; hazard ratio [HR], 0.81; 95% CI, 0.72 to 0.91; P < .001), with no significant heterogeneity among trials (P = .39; I-2 = 2%). No significant interaction effect between treatment arm and investigated characteristics was demonstrated. Patients assigned to FOLFOXIRI + bevacizumab had longer PFS (median, 12.2 v 9.9 months; HR, 0.74; 95% CI, 0.67 to 0.82; P < .001), higher ORR (64.5% v 53.6%; P < .001), higher R0 resection rate (16.4% v 11.8%; P = .007), and higher rates of grade 3/4 neutropenia (45.8% v 21.5%; P < .001), febrile neutropenia (6.3% v 3.7%; P = .019), and diarrhea (17.8% v 8.4%; P < .001).CONCLUSIONFOLFOXIRI + bevacizumab significantly and meaningfully improves survival of patients with metastatic colorectal cancer compared with doublets + bevacizumab and provides advantage in PFS, ORR, and R0 resection rate at the price of a moderate increase in toxicity. No increased benefit is observed among patients with BRAF-mutant tumors.