Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.
Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation.
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DOI：
10.1158/2159-8290.cd-16-0050
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发表时间：
2016-12
期刊：
影响因子：
28.2
通讯作者：
Kopetz S
中科院分区：
文献类型：
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作者：
Hong DS;Morris VK;El Osta B;Sorokin AV;Janku F;Fu S;Overman MJ;Piha-Paul S;Subbiah V;Kee B;Tsimberidou AM;Fogelman D;Bellido J;Shureiqi I;Huang H;Atkins J;Tarcic G;Sommer N;Lanman R;Meric-Bernstam F;Kopetz S
在体外，EGFR抑制剂与BRAF抑制剂维罗非尼联合使用，可对BRAFV600 E转移性结直肠癌（mCRC）产生协同细胞毒性，伊立替康可进一步增强细胞毒性。维罗非尼、伊立替康和西妥昔单抗在BRAF突变的恶性肿瘤中的安全性和疗效尚未确定。在这项3+3 I期研究中，BRAFV600 E晚期实体癌患者接受西妥昔单抗和伊立替康以及剂量递增的维罗非尼治疗。入组了19例患者（18例mCRC，1例阑尾癌）。3例患者出现剂量限制性毒性。维罗非尼的最大耐受剂量为960 mg，每日两次。根据RECIST 1.1标准，17例可评价患者中有6例（35%）达到放射学缓解，与体内模型一致，证明三联方案的肿瘤消退。中位无进展生存期为7.7个月。BRAFV600E cfDNA趋势与放射学变化相关，并且在进展时观察到来自cfDNA的基因中的获得性突变重新激活MAPK信号传导。
In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer (mCRC), further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with mCRC, 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The maximum tolerated dose of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by RECIST 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E cfDNA trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.