encorafenib、binimetinib 和西妥昔单抗治疗 V600E 突变型结直肠癌。
Encorafenib, Binimetinib, and Cetuximab in V600E-Mutated Colorectal Cancer.
机构信息
From the University of Texas M.D. Anderson Cancer Center, Houston (S.K., V.M.); West Cancer Center and Research Institute, OneOncology, Germantown, TN (A. Grothey); Memorial Sloan Kettering Cancer Center, New York (R.Y., A.K.); University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium (E.V.C., J. Dekervel); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (J. Desai, C.G.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); Hammersmith Hospital, Division of Cancer, Imperial College London (H.W.), and the Sarah Cannon Research Institute and University College London Cancer Institute (H.-T.A.), London, and the Christie NHS Foundation Trust/National Institute for Health Research Manchester Biomedical Research Centre, Manchester (M.B.) - all in the United Kingdom; the University of Campania Luigi Vanvitelli, Naples (F.C.), and Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua (F.L., S.L.) - both in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (Y.S.H., T.-W.K.); the Netherlands Cancer Institute, Amsterdam (N.S., J.H.M.S.); Oslo University Hospital, Oslo (T.K.G.); Hospital Gregorio Marañón, Madrid (P.G.-A., A.C.F.), and Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, UVic, IOB-Quiron, Barcelona (E.E., J.T.) - both in Spain; Odense University Hospital, Odense, Denmark (P.P., L.S.T.); Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia (S.O.); and Array BioPharma, Boulder, CO (A. Gollerkeri, C.K., K.M., M.P., J.C.-B., L.A., V.S.).
出版信息
N Engl J Med. 2019 Oct 24;381(17):1632-1643. doi: 10.1056/NEJMoa1908075. Epub 2019 Sep 30.
BACKGROUND
Patients with metastatic colorectal cancer with the 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 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 V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
背景
携带 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。单独抑制 BRAF 因表皮生长因子受体信号通路的重新激活而仅有有限的活性。
方法
在这项开放标签、3 期临床试验中，我们招募了 665 名携带 V600E 突变的转移性结直肠癌患者，这些患者在接受一种或两种先前治疗方案后疾病进展。患者以 1:1:1 的比例随机分配接受恩考芬尼、比美替尼和西妥昔单抗（三联治疗组）；恩考芬尼和西妥昔单抗（双药治疗组）；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）。主要终点是三联治疗组与对照组的总生存期和客观缓解率。次要终点是双药治疗组与对照组的总生存期。我们在此报告了预先指定的中期分析结果。
结果
三联治疗组的中位总生存期为 9.0 个月，对照组为 5.4 个月（死亡风险比，0.52；95%置信区间[CI]，0.39 至 0.70；P<0.001）。三联治疗组的确认缓解率为 26%（95%CI，18 至 35），对照组为 2%（95%CI，0 至 7）（P<0.001）。双药治疗组的中位总生存期为 8.4 个月（死亡风险比对照，0.60；95%CI，0.45 至 0.79；P<0.001）。三联治疗组 58%的患者发生 3 级或更高级别的不良事件，双药治疗组 50%的患者和对照组 61%的患者发生。
结论
在携带 V600E 突变的转移性结直肠癌患者中，与标准治疗相比，恩考芬尼、西妥昔单抗和比美替尼的联合治疗显著延长了总生存期并提高了缓解率。（由 Array BioPharma 等资助；BEACON CRC 临床试验.gov 编号，NCT02928224；EudraCT 编号，2015-005805-35。）
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