Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study
Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study
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DOI：
10.1038/bjc.2017.93
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发表时间：
2017-05-09
影响因子：
8.8
通讯作者：
Tveit, Kjell Magne
中科院分区：
文献类型：
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作者：
Guren, Tormod Kyrre;Thomsen, Maria;Tveit, Kjell Magne
背景：Nordic - vii研究是一项西妥昔单抗联合连续或间歇性氟尿嘧啶、亚叶酸和奥沙利铂（Nordic FLOX）与单独使用FLOX一线治疗转移性结直肠癌的随机III期试验。本报告在初步分析后5年更新了BRAF和扩展RAS突变状态的最终生存分析。方法：共有566例患者被纳入NORDIC-VII研究的意向治疗（ITT）人群。在初步生存分析中，从176名患者中获得了最新的生存状态。先前发现的223个肿瘤样本为KRAS（外显子2）和BRAF （V600E）野生型，重新分析KRAS（外显子3和4）和NRAS（外显子2-4）突变。结果：包括扩展的RAS分析，从457例患者（占ITT人群的81%）中获得RAS和BRAF突变状态。46%的肿瘤发生RAS突变，12%的肿瘤发生BRAF突变。RAS和BRAF如果发生突变，则为不良预后因素。最新的分析证实了最初报告的发现，即西妥昔单抗与FLOX联合使用对RAS/BRAF野生型肿瘤患者的无进展生存期和总生存期都没有任何额外的益处。然而，在前8个治疗周期后，单独接受西妥昔单抗的一部分患者的结果表明，西妥昔单抗单药治疗有有益的效果。结论：在Nordic FLOX中加入西妥昔单抗并没有提供任何临床益处，但数据表明西妥昔单抗单药治疗在Nordic - vii队列中RAS/BRAF野生型肿瘤患者中有效果。这些数据与西妥昔单抗与北欧FLOX化疗主干之间的负相互作用相一致。
Background: The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.Methods: A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.Results: Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.Conclusions: Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.