Elez Elena, Yoshino Takayuki, Shen Lin, Lonardi Sara, Van Cutsem Eric, Eng Cathy, Kim Tae Won, Wasan Harpreet Singh, Desai Jayesh, Ciardiello Fortunato, Yaeger Rona, Maughan Timothy S, Morris Van K, Wu Christina, Usari Tiziana, Laliberte Robert, Dychter Samuel S, Zhang Xiaosong, Tabernero Josep, Kopetz Scott
Vall d'Hebron Hospital Campus, Barcelona.
Vall d'Hebron Institute of Oncology, Barcelona.
N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi: 10.1056/NEJMoa2501912. Epub 2025 May 30.
First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.
We randomly assigned patients with untreated V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.
Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.
This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.).
在一项开放标签的3期试验中，将恩考芬尼联合西妥昔单抗（EC）联合或不联合化疗（奥沙利铂、亚叶酸钙和氟尿嘧啶[mFOLFOX6]）用于治疗V600E突变的转移性结直肠癌（一种预后较差的侵袭性亚型）与标准治疗（化疗联合或不联合贝伐单抗）进行了比较，该试验在两个主要终点之一上显示出显著性差异，即根据盲法独立中央审查的客观缓解率（EC + mFOLFOX6与标准治疗的优势比为2.44；单侧P < 0.001）。这一结果促使美国食品药品监督管理局加速批准了这种用于V600E突变转移性结直肠癌的研究性联合疗法，包括作为一线治疗。目前已有无进展生存期（第二个主要终点）的数据以及总生存期的更新期中分析数据。
我们将未经治疗的V600E突变转移性结直肠癌患者随机分配接受EC、EC + mFOLFOX6或标准治疗。两个主要终点是客观缓解率（先前已报告）以及EC + mFOLFOX6组和标准治疗组根据盲法独立中央审查的无进展生存期。关键次要终点是总生存期。
与标准治疗相比，EC + mFOLFOX6组的无进展生存期显著更长（中位数分别为12.8个月和7.1个月；进展或死亡的风险比为0.53；95%置信区间[CI]为0.41至0.68；P < 0.001）。在期中分析中，EC + mFOLFOX6组的总生存期也显著长于标准治疗组（中位数分别为30.3个月和15.1个月；死亡风险比为0.49；95%CI为0.38至0.63；P < 0.001）。治疗期间严重不良事件的发生率在EC + mFOLFOX6组为46.1%，在标准治疗组为38.9%。安全性特征与每种药物已知的特征一致。
该试验表明，对于V600E突变的转移性结直肠癌患者，一线使用EC + mFOLFOX6治疗的无进展生存期和总生存期显著长于标准治疗。（由辉瑞公司等资助；BREAKWATER临床试验注册号，NCT04607421。）
