BACKGROUND Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

中文翻译：

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Encorafenib，Binimetinib和Cetuximab在BRAF V600E突变的结直肠癌中的作用。

背景具有BRAF V600E突变的转移性结直肠癌患者预后较差，初始治疗失败后中位总生存期为4至6个月。由于通过表皮生长因子受体信号传导的途径重新激活，单独抑制BRAF具有有限的活性。方法在这项开放标签的3期试验中，我们招募了665例患有BRAF V600E突变的转移性结直肠癌的患者，这些患者在接受一，两种方案后病情发展。患者按照1：1 1：1的比例随机分配接受恩可拉非尼，比美替尼和西妥昔单抗（三联疗法治疗组）；恩可拉非尼和西妥昔单抗（双重治疗组）；或研究者选择西妥昔单抗和伊立替康或西妥昔单抗和FOLFIRI（亚叶酸，氟尿嘧啶和伊立替康）（对照组）。与对照组相比，三联疗法组的主要终点是总体生存率和客观缓解率。次要终点是双重治疗组与对照组相比的总生存期。我们在这里报告预先指定的中期分析的结果。结果三联疗法组中位总生存期为9.0个月，对照组为5.4个月（死亡风险比为0.52； 95％置信区间[CI]为0.39至0.70； P <0.001）。三联疗法组确认的应答率为26％（95％CI，18至35），对照组为2％（95％CI，0至7）（P <0.001）。双重疗法治疗组中位总生存期为8.4个月（死亡与对照组的危险比为0.60； 95％CI为0.45至0.79； P <0.001）。三联疗法组中58％的患者发生3级或更高级别的不良事件，双联疗法组中50％的患者和对照组中的61％发生。结论与BRAF V600E突变的转移性结直肠癌患者相比，encorafenib，西妥昔单抗和binimetinib的组合可显着延长标准化疗的总生存期和更高的应答率。（由Array BioPharma等投资; BEACON CRC ClinicalTrials.gov编号，NCT02928224; EudraCT编号，2015-005805-35。）与转移疗法相比，BRAF V600E突变的转移性结直肠癌患者比奈替尼可显着延长总生存期，并具有比标准疗法更高的缓解率。（由Array BioPharma等投资; BEACON CRC ClinicalTrials.gov编号，NCT02928224; EudraCT编号，2015-005805-35。）与转移疗法相比，BRAF V600E突变的转移性结直肠癌患者比奈替尼可显着延长总生存期，并具有比标准疗法更高的缓解率。（由Array BioPharma等投资; BEACON CRC ClinicalTrials.gov编号，NCT02928224; EudraCT编号，2015-005805-35。）