University of Texas MD Anderson Cancer Center, Houston, TX.
SWOG Statistical and Data Management Center, Seattle, WA.
J Clin Oncol. 2021 Feb 1;39(4):285-294. doi: 10.1200/JCO.20.01994. Epub 2020 Dec 23.
mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab.
One hundred six patients with -mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily).
Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, = .001). The response rate was 17% versus 4% ( = .05), with a disease control rate of 65% versus 21% ( < .001). A decline in circulating tumor DNA variant allele frequency was seen in 87% versus 0% of patients ( < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype.
Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in -mutated CRC.
在转移性结直肠癌（CRC）患者中，突变很少与 BRAF 抑制剂 vemurafenib 的客观应答相关。vemurafenib 阻断导致 EGFR 的反馈上调，其信号转导活性可被 cetuximab 阻断。
106 例先前接受过一种或两种方案治疗的 -突变转移性 CRC 患者被随机分配接受伊立替康和 cetuximab 联合或不联合 vemurafenib（960 mg PO，每日 2 次）。
无进展生存期（主要终点）随 vemurafenib 的加入而改善（风险比，0.50，P =.001）。应答率分别为 17%和 4%（P =.05），疾病控制率分别为 65%和 21%（P <.001）。87%的患者循环肿瘤 DNA 变异等位基因频率下降，而 0%的患者下降（P <.001），在进展时发生获得性 RAS 改变的发生率较低。RNA 分析表明，治疗获益不依赖于先前确定的 BRAF 亚组或共识分子亚型。
同时抑制 EGFR 和 BRAF 联合伊立替康对 -突变 CRC 有效。
