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
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; University of Chicago Cancer Research Center, Chicago, IL, USA.
Lancet Oncol. 2009 Mar;10(3):247-57. doi: 10.1016/S1470-2045(09)70002-6. Epub 2009 Feb 7.
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. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab.
Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913.
In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue.
The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.
表皮生长因子受体（EGFR）是头颈部鳞状细胞癌已获验证的治疗靶点，但在复发或转移性疾病患者中，EGFR靶向药物疗效一般。血管内皮生长因子（VEGF）介导的血管生成被认为是抗EGFR治疗耐药的一种机制。在这项多机构的I/II期研究中，我们将EGFR抑制剂厄洛替尼与抗VEGF抗体贝伐单抗联合使用。
2003年4月15日至2005年1月27日，从美国7个中心招募复发性或转移性头颈部鳞状细胞癌患者，给予厄洛替尼（每日150mg）和剂量递增的贝伐单抗。I期和II期研究的主要目标分别是确定与厄洛替尼联合使用时贝伐单抗的最大耐受剂量和剂量限制性毒性，以及确定客观缓解率和疾病进展时间。分别通过酶联免疫吸附测定和免疫荧光定量激光分析收集和分析治疗前的血清和组织。本研究已在ClinicalTrials.gov注册，编号为NCT00055913。
在试验的I期研究中，10名患者被纳入3个连续队列，未观察到剂量限制性毒性。46名患者在试验的II期研究中（包括I期研究中的3名患者）接受最高剂量的贝伐单抗（每3周15mg/kg）。在方案规定的46名患者之外又纳入了2名患者，II期评估共有48名患者。任何级别的最常见毒性反应是皮疹和腹泻（分别为48名患者中的41名和16名）。3名患者发生3级或更高级别的严重出血事件。7名患者有反应，4名完全缓解，从而否定了无效假设。总生存期和无进展生存期（PFS）的中位时间分别为7.1个月（95%CI 5.7 - 9.0）和4.1个月（2.8 - 4.4）。在11名有可用组织的患者亚组中，治疗前活检中肿瘤细胞磷酸化VEGF受体-2（pVEGFR2）与总VEGFR2的较高比值以及内皮细胞pEGFR与总EGFR的较高比值分别与完全缓解（0.704对0.386，p = 0.036以及0.949对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使用对头颈部复发性或转移性鳞状细胞癌耐受性良好。少数患者似乎获得了持续益处，完全缓解与治疗前肿瘤组织中假定靶点的表达相关。
