Hong David S, Morris Van K, El Osta Badi, Sorokin Alexey V, Janku Filip, Fu Siqing, Overman Michael J, Piha-Paul Sarina, Subbiah Vivek, Kee Bryan, Tsimberidou Apostolia M, Fogelman David, Bellido Jorge, Shureiqi Imad, Huang Helen, Atkins Johnique, Tarcic Gabi, Sommer Nicolas, Lanman Richard, Meric-Bernstam Funda, Kopetz Scott
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2016 Dec;6(12):1352-1365. doi: 10.1158/2159-8290.CD-16-0050. Epub 2016 Oct 11.
In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAF metastatic colorectal cancer, 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 BRAF-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAF circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.
Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAF metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.
在体外，表皮生长因子受体（EGFR）抑制与BRAF抑制剂维莫非尼联合使用，对BRAF转移性结直肠癌具有协同细胞毒性作用，伊立替康可进一步增强该作用。维莫非尼、伊立替康和西妥昔单抗在BRAF突变恶性肿瘤中的安全性和疗效尚未明确。在这项3+3设计的I期研究中，BRAF晚期实体癌患者接受西妥昔单抗和伊立替康，并逐步增加维莫非尼剂量。共入组19例患者（18例转移性结直肠癌患者和1例阑尾癌患者）。3例患者出现剂量限制性毒性反应。维莫非尼的最大耐受剂量为每日两次，每次960 mg。按照实体瘤疗效评价标准1.1标准，17例可评估患者中有6例（35%）获得影像学缓解，这与体内模型显示三联方案可使肿瘤消退一致。中位无进展生存期为7.7个月。BRAF循环游离DNA（cfDNA）趋势与影像学变化相关，且在疾病进展时观察到cfDNA中重新激活丝裂原活化蛋白激酶（MAPK）信号通路的基因出现获得性突变。
维莫非尼联合伊立替康和西妥昔单抗在难治性BRAF突变转移性结直肠癌患者中耐受性良好，生存结果和缓解率均超过先前关于维莫非尼以及伊立替康加西妥昔单抗用于BRAF转移性结直肠癌的报道。与单独使用维莫非尼和西妥昔单抗相比，体内模型显示三联方案可使肿瘤消退。cfDNA可预测影像学缓解，并在疾病进展时识别重新激活MAPK通路的突变。《癌症发现》；6(12)；1352 - 65。©2016美国癌症研究协会。本文在本期特刊第1293页重点介绍。
