FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study
FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study
复制标题
DOI：
10.1016/s1470-2045(15)00122-9
复制
发表时间：
2015-10-01
期刊：
影响因子：
51.1
通讯作者：
Falcone, Alfredo
中科院分区：
文献类型：
--
作者：
Cremolini, Chiara;Loupakis, Fotios;Falcone, Alfredo
在TRIBE研究中，与FOLFIRI（氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康）联合贝伐单抗相比，FOLFOXIRI（氟尿嘧啶、亚叶酸和伊立替康）联合贝伐单抗显著改善了转移性结直肠癌患者的无进展生存期。在这项更新的分析中，我们的目的是提供总生存率的成熟结果-次要终点-并报告RAS和BRAF分子亚组的治疗效果。III期患者随机化研究（年龄18-70岁，东部肿瘤协作组[ECOG]体能状态评分≤ 2，年龄71-75岁，ECOG体能状态评分为0）来自34个意大利肿瘤单位的不可切除的转移性结直肠癌患者。患者通过基于网络的程序随机分配（1：1）接受FOLFIRI+贝伐珠单抗或FOLFOXIRI+贝伐珠单抗。贝伐珠单抗以5 mg/kg静脉给药。FOLFIRI包括伊立替康180 mg/m2静脉输注60 min，随后甲酰四氢叶酸200 mg/m2静脉输注120 min，氟尿嘧啶400 mg/m2静脉推注，氟尿嘧啶2400 mg/m2持续输注46 h。FOLFOXIRI包括伊立替康165 mg/m2静脉输注60 min，随后奥沙利铂85 mg/m2静脉输注120 min，同时给予亚叶酸200 mg/m2，随后氟尿嘧啶3200 mg/m2持续输注48 h。集中采集用于RAS和BRAF突变状态分析的组织样本。在这项更新的分析中，我们评估了主要队列中总生存期的次要终点以及RAS和BRAF分子亚组的治疗疗效。TRIBE于2014年11月30日结束。结果2008年7月17日至2011年5月31日，508例患者被随机分配。中位随访48.1个月（IQR 41.7-55.6），FOLFOXIRI+贝伐珠单抗组的中位总生存期为29.8个月（95%CI 26.0-34.3），而FOLFIRI+贝伐珠单抗组为25.8个月（22.5-29.1）（风险比[HR] 0.80，95%CI 0.65-0.98; p=0.03）。中位总生存期为37.1个月RAS和BRAF野生型亚组（95% CI 29.7-42.7）与25.6个月RAS突变阳性亚组（22.4-28.6）（HR 1.49，95% CI 1.11-1.99）和13.4个月（8.2-24.1）（HR 2.79，95% CI 1.75-4.46;似然比检验p< 0.0001）。治疗效果在分子亚组间无显著差异（p（相互作用）= 0.52）。无论基线临床特征和RAS或BRAF突变状态如何，对于符合本研究入选标准的患者，FOLFOXIRI加贝伐珠单抗是一种可行的治疗选择。
Background In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups.Methods TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014.Findings Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48.1 months (IQR 41.7-55.6), median overall survival was 29.8 months (95% CI 26.0-34.3) in the FOLFOXIRI plus bevacizumab group compared with 25.8 months (22.5-29.1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0.80, 95% CI 0.65-0.98; p=0.03). Median overall survival was 37.1 months (95% CI 29.7-42.7) in the RAS and BRAF wild-type subgroup compared with 25.6 months (22.4-28.6) in the RAS-mutation-positive subgroup (HR 1.49, 95% CI 1.11-1.99) and 13.4 months (8.2-24.1) in the BRAF-mutation-positive subgroup (HR 2.79, 95% CI 1.75-4.46; likelihood-ratio test p< 0.0001). Treatment effect was not significantly different across molecular subgroups (p(interaction) = 0.52).Interpretation FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.