Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.
Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.
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DOI：
10.1016/s1470-2045(09)70002-6
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发表时间：
2009-03
期刊：
影响因子：
51.1
通讯作者：
Vokes, Everett E.
中科院分区：
文献类型：
--
作者：
Cohen, Ezra E. W.;Davis, Darren W.;Karrison, Theodore G.;Seiwert, Tanguy Y.;Wong, Stuart J.;Nattam, Sreenivasa;Kozloff, Mark F.;Clark, Joseph I.;Yan, Duen-Hwa;Liu, Wen;Pierce, Carolyn;Dancey, Janet E.;Stenson, Kerstin;Blair, Elizabeth;Dekker, Allison;Vokes, Everett E.
表皮生长因子受体（EGFR）是头颈部鳞状细胞癌的有效靶标，但在复发或转移性疾病患者中，EGFR靶向药物显示出适度的疗效。血管内皮生长因子（VEGF）介导的血管生成被认为是抵抗抗egfr治疗的一种机制。该研究将EGFR抑制剂厄洛替尼与抗vegf抗体贝伐单抗联合使用。这项多机构I/II期研究招募了头颈部复发或转移性鳞状细胞癌患者，在递增剂量队列中接受厄洛替尼（150mg /天）和贝伐单抗治疗。I期和II期的主要目标分别是确定贝伐单抗与厄洛替尼联合使用时的最大耐受剂量和剂量限制性毒性，并确定客观反应率和疾病进展时间。采集治疗前血清和组织，分别采用酶联免疫吸附法和免疫荧光定量激光分析法进行分析。本研究已在ClinicalTrials.gov注册，编号NCT00055913。I期部分在三个连续队列中招募了10名受试者，未观察到剂量限制性毒性。另外46名受试者以II期剂量（贝伐单抗15mg /kg每3周）入组。所有级别中最常见的毒性是皮疹和腹泻（48例受试者中分别有41例和16例）。3例患者出现严重出血事件。观察到的应答率为15%，其中4个完全应答（CR）允许拒绝原假设。中位总生存期和无进展生存期（PFS）分别为7.1个月（95%可信区间：5.7至9.0）和4.1个月（95%可信区间：2.8至4.4）。在11名有可用组织的受试者中，预处理活检中磷酸化超过总VEGF受体-2和EGFR的比例较高与CR（分别为0.7043比0.3857,p=0.036和0.949比0.332,p=0.036）和肿瘤缩小（分别为p=0.007和p=0.008）相关。厄洛替尼和贝伐单抗联合治疗头颈部复发或转移性鳞状细胞癌耐受性良好。一些患者似乎获得了持续的益处，完全缓解与治疗前肿瘤组织中假定靶点的表达有关。
The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma of the head and neck but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF) mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. This study combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. This multi-institutional phase I/II study enrolled patients with recurrent or metastatic squamous cell carcinoma of the head and neck to receive erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II portions, respectively, were to determine the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to determine the objective response rate and time to disease progression. Pre-treatment serum and tissues were collected and analyzed by Enzyme-Linked ImmunoSorbent Assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. The phase I portion enrolled 10 subjects in three successive cohorts without dose-limiting toxicity observed. An additional 46 subjects were enrolled at the phase II dose (bevacizumab 15 mg/kg every 3 weeks). The most common toxicities of any grade were rash and diarrhea (41 and 16 of 48 subjects, respectively). Three patients experienced serious bleeding events. The observed response rate was 15% with 4 complete responses (CR) allowing rejection of the null hypothesis. The median overall and progression-free survival (PFS) durations were 7.1 (95% Confidence Interval: 5.7 to 9.0) and 4.1 (95% Confidence Interval: 2.8 to 4.4) months, respectively. Higher ratios of phosphorylated over total VEGF receptor-2 and EGFR in pre-treatment biopsies were associated with CR (0.7043 vs. 0.3857, p=0.036 and 0.949 vs. 0.332, p=0.036, respectively) and tumor shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 subjects with available tissue. The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous cell carcinoma of the head and neck. Some patients appear to derive a sustained benefit and complete responses were associated with expression of putative targets in pre-treatment tumor tissue.