Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer The UNICANCER PRODIGE18 Randomized Clinical Trial
Continuation of Bevacizumab vs Cetuximab Plus Chemotherapy After First Progression in KRAS Wild-Type Metastatic Colorectal Cancer The UNICANCER PRODIGE18 Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2018.4465
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发表时间：
2019-01-01
期刊：
影响因子：
28.4
通讯作者：
Borg, Christophe
中科院分区：
文献类型：
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作者：
Bennouna, Jaafar;Hiret, Sandrine;Borg, Christophe
重要二线化疗加贝伐单抗或西妥昔单抗是治疗转移性结直肠癌的有效选择。目的评价化疗加贝伐单抗与西妥昔单抗联合化疗后转移性结直肠癌患者4个月无进展生存率(PFS)。设计、背景和参与者从2010年12月14日至2015年5月5日进行了一项前瞻性、开放标签、多中心、随机的2期试验。在野生型KRAS外显子2转移性结直肠癌患者中，主要的资格标准是贝伐单抗联合氟尿嘧啶联合伊立替康或奥沙利铂治疗后的疾病进展。干预患者被随机分为A组(FOLFIRI[氟尿嘧啶和亚叶酸联合伊立替康]或改良FOLFOX6[氟尿嘧啶和亚叶酸联合奥沙利铂]+贝伐单抗)或B组(FOLFIRI或改良FOLFOX6+西妥昔单抗)；二线化疗方案根据一线治疗(交叉)选择。MAIN结果和衡量主要终点为4个月的PFS率。次要终点包括安全性、客观缓解率、总存活率和PFS。结果共有132名患者(47名女性和85名男性；中位年龄63.0岁[范围33.0-84.0岁]；74名东部合作肿瘤组表现状态为0的患者、54名表现状态为1的患者和4名表现状态未知的患者)在25个地点纳入研究。中位PFS分别为7.1个月(95%CI，5.7~8.2个月)和5.6个月(95%CI，4.2~6.5个月)(危险度0.71；95%CI，0.50~1.02；A组和B组的中位总生存期分别为15.8个月(95%CI，9.5-22.3个月)和10.4个月(95%CI，7.0-16.2个月)(风险比，0.69；95%CI，0.46-1.04；P=0.08)。对95例肿瘤标本进行了KRAS(外显子2、3和4)、NRAS(外显子2、3和4)和BRAF(V600)的中心分析。81名患者有野生型KRAS和野生型NRAS肿瘤。结论和相关性PRODIGE18(Partenariary de Recherche en Oncolgie消化系统)研究的结果显示没有显著差异，但对于一线贝伐单抗加化疗进展的野生型RAS转移性结直肠癌患者，支持继续贝伐单抗与化疗交叉。
IMPORTANCE Second-line treatment with chemotherapy plus bevacizumab or cetuximab is a valid option for metastatic colorectal cancer.OBJECTIVE To evaluate the progression-free survival (PFS) rate at 4 months with chemotherapy plus bevacizumab vs cetuximab for patients with progression of metastatic colorectal cancer after bevacizumab plus chemotherapy.DESIGN, SETTING, AND PARTICIPANTS A prospective, open-label, multicenter, randomized phase 2 trial was conducted from December 14, 2010, to May 5, 2015. The main eligibility criterion was disease progression after bevacizumab plus fluorouracil with irinotecan or oxaliplatin in patients with wild-type KRAS exon 2 metastatic colorectal cancer. All analyses were performed on the modified intent-to-treat population.INTERVENTIONS Patients were randomized to arm A (FOLFIRI [fluorouracil and folinic acid combined with irinotecan] or modified FOLFOX6 [fluorouracil and folinic acid combined with oxaliplatin] plus bevacizumab) or arm B (FOLFIRI or modified FOLFOX6 plus cetuximab); the second-line chemotherapy regimen was chosen according to first-line treatment (crossover).MAIN OUTCOMES AND MEASURES The primary end pointwas the 4-month PFS rate. Secondary end points included safety, objective response rate, overall survival, and PFS.RESULTS A total of 132 patients (47 women and 85 men; median age, 63.0 years [range, 33.0-84.0 years]; 74 patients with an Eastern Cooperative Oncology Group performance status of 0, 54 patients with a performance status of 1, and 4 patients with unknown performance status) were included at 25 sites. The 4-month PFS rate was 80.3% (95% CI, 68.0%-88.3%) in arm A and 66.7% (95% CI, 53.6%-76.8%) in arm B. The median PFS was 7.1 months (95% CI, 5.7-8.2 months) in arm A and 5.6 months (95% CI, 4.2-6.5 months) in arm B (hazard ratio, 0.71; 95% CI, 0.50-1.02; P = .06), and the median overall survival was 15.8 months (95% CI, 9.5-22.3 months) in arm A and 10.4 months (95% CI, 7.0-16.2 months) in arm B (hazard ratio, 0.69; 95% CI, 0.46-1.04; P = .08). A central analysis of KRAS (exons 2, 3, and 4), NRAS (exons 2, 3, and 4), and BRAF (V600) was performed for 95 tumor samples. Eighty-one patients had wild-type KRAS and wild-type NRAS tumors.CONCLUSIONS AND RELEVANCE The results of the PRODIGE18 (Partenariat de Recherche en Oncologie DIGEstive) study showed a nonsignificant difference but favored continuation of bevacizumab with chemotherapy crossover for patients with wild-type RAS metastatic colorectal cancer that progressed with first-line bevacizumab plus chemotherapy.