近日，西班牙瓦尔德希伯伦大学医院Josep Tabernero教授及其课题组研究了Encorafenib+Binimetinib+西妥昔单抗治疗BRAF V600E突变的结直肠癌的效果。2019年9月29日，《新英格兰医学杂志》在线发表了这项成果。

在这项开放标签、临床3期的试验中，研究组招募了665例BRAF V600E突变的转移性结直肠癌患者，这些患者此前接受过一两个治疗方案但仍疾病进展。患者按1：1 ：1随机分组接受Encorafenib+Binimetinib+西妥昔单抗（三联治疗组）；Encorafenib+西妥昔单抗（双联治疗组）；西妥昔单抗+伊立替康或西妥昔单抗+FOLFIRI（叶酸，氟尿嘧啶和伊立替康）（对照组）。

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，死亡风险比为0.52。三联治疗组的缓解率为26% ，对照组为2%，差异显著。双联治疗组的中位总生存期为8.4个月，与对照组相比，死亡风险比为0.60。三联治疗组中3级及以上不良事件的发生率为58%，双联治疗组为50%，对照组为61%。

综上，Encorafenib+西妥昔单抗+Binimetinib可大大延长BRAF V600E突变的转移性结直肠癌患者的总生存期，并提高缓解率。

据悉，BRAF V600E突变的转移性结直肠癌患者预后不良，初始治疗失败后中位总生存期为4-6个月。由于表皮生长因子受体信号通路的激活，单用BRAF抑制剂效果有限。

附：英文原文

Title: Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer

Author: Scott Kopetz, Axel Grothey, Rona Yaeger, Eric Van Cutsem, Jayesh Desai, Takayuki Yoshino, Harpreet Wasan, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong, Neeltje Steeghs, Tormod K. Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso, Per Pfeiffer, Sergey Orlov, Sara Lonardi, Elena Elez, Tae-Won Kim, Jan H.M. Schellens, Christina Guo, Asha Krishnan, Jeroen Dekervel, Van Morris, Aitana Calvo Ferrandiz, L.S. Tarpgaard, Michael Braun, Ashwin Gollerkeri, Christopher Keir, Kati Maharry, Michael Pickard, Janna Christy-Bittel, Lisa Anderson, Victor Sandor, Josep Tabernero

Issue&Volume: 2019-09-29

Abstract:

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.

DOI: 10.1056/NEJMoa1908075

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1908075