三種靶向藥聯(lián)合治療BRAF V600E突變的結(jié)直腸癌
2019-09-30
來(lái)源：小柯機(jī)器人
近日，西班牙瓦爾德希伯倫大學(xué)醫(yī)院Josep Tabernero教授及其課題組研究了Encorafenib+Binimetinib+西妥昔單抗治療BRAF V600E突變的結(jié)直腸癌的效果。2019年9月29日，《新英格蘭醫(yī)學(xué)雜志》在線發(fā)表了這項(xiàng)成果。
在這項(xiàng)開(kāi)放標(biāo)簽、臨床3期的試驗(yàn)中，研究組招募了665例BRAF V600E突變的轉(zhuǎn)移性結(jié)直腸癌患者，這些患者此前接受過(guò)一兩個(gè)治療方案但仍疾病進(jìn)展。患者按1：1 ：1隨機(jī)分組接受Encorafenib+Binimetinib+西妥昔單抗（三聯(lián)治療組）；Encorafenib+西妥昔單抗（雙聯(lián)治療組）；西妥昔單抗+伊立替康或西妥昔單抗+FOLFIRI（葉酸，氟尿嘧啶和伊立替康）（對(duì)照組）。
三聯(lián)治療組的中位總生存期為9.0個(gè)月，對(duì)照組為5.4個(gè)月，死亡風(fēng)險(xiǎn)比為0.52。三聯(lián)治療組的緩解率為26% ，對(duì)照組為2%，差異顯著。雙聯(lián)治療組的中位總生存期為8.4個(gè)月，與對(duì)照組相比，死亡風(fēng)險(xiǎn)比為0.60。三聯(lián)治療組中3級(jí)及以上不良事件的發(fā)生率為58%，雙聯(lián)治療組為50%，對(duì)照組為61%。
綜上，Encorafenib+西妥昔單抗+Binimetinib可大大延長(zhǎng)BRAF V600E突變的轉(zhuǎn)移性結(jié)直腸癌患者的總生存期，并提高緩解率。
據(jù)悉，BRAF V600E突變的轉(zhuǎn)移性結(jié)直腸癌患者預(yù)后不良，初始治療失敗后中位總生存期為4-6個(gè)月。由于表皮生長(zhǎng)因子受體信號(hào)通路的激活，單用BRAF抑制劑效果有限。
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
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