波士顿——一项检验brivanib和索拉非尼作为晚期肝细胞癌一线治疗药物的Ⅲ期试验显示，抗血管增生在研药物brivanib未能达到相对于索拉非尼的非劣效性标准。

目前美国食品药品管理局(FDA)已批准的唯一晚期肝细胞癌(HCC)一线用药为索拉非尼(多吉美)，人们期待着较索拉非尼更有效和耐受性更好的药物。尤其是在亚太地区和撒哈拉沙漠以南等HCC患病率最高的国家，“很多患者在诊断时已为晚期疾病，因而已无可治愈的方法”，英格兰伯明翰大学肿瘤学与转化研究教授兼英国肿瘤研究临床试验小组的Philip Johnson博士在美国肝病研究学会(AASLD)年会上指出。

Johnson博士及其同事将1,155例患者随访分配到双盲的索拉非尼(一种多靶向激酶抑制剂)组或brivanib[一种血管内皮生长因子(VEGF)和成纤维细胞生长因子(FGF)双重受体抑制剂]组。受试者此前未接受任何全身性治疗，平均年龄约为60岁，多数为男性(84%)。大约2/3的患者为亚裔，92%为Child-Pugh A级。两组患者的乙型肝炎(20%)或丙型肝炎(45%)感染以及酒精性肝病(16%)患病率相似。

这项试验名为BRISK-FL研究，设计为非劣效性/有效性混合，研究者设定的非劣效性上限为1.08，相当于中位总生存期的差异不超过3周。这保证了在使用brivanib期间的死亡风险不会不可接受地高于索拉非尼。基于样本量，非劣效性边界1.08意味着，对于brivanib而言，估计危险比必须不超过0.94方可视为相对于索拉非尼具有非劣效性。

两组中位总生存期的比较显示，brivanib的总危险比为1.07，95%置信区间上限为1.23，高于预先设定的非劣效性边界——≤1.08。索拉非尼和brivanib组的中位总生存期分别为9.9个月和9.5个月。在各个亚组中，均无一种药物表现出明显的生存期优势。接受索拉非尼和brivanib治疗的患者的中位至进展时间几乎相同，分别为4.1个月和4.2个月。两组的完全、部分和总应答率以及疾病控制率均相似。270例接受索拉非尼治疗的患者和250例接受brivanib治疗的患者中，分别有31%和58%的甲胎蛋白水平降低≥50%。Johnson博士称，甲胎蛋白水平降低是肿瘤细胞被杀死的一种指标。

两组中有相似百分率的患者药物减量或接受研究后治疗。两组停用研究药物的患者比例相似；最常见的原因为疾病进展和药物毒性反应。两种药物的总体不良事件发生率相似，但接受brivanib治疗患者的食欲减退、疲倦、高血压、恶心、呕吐和低钠血症的发生率显著增高。在索拉非尼治疗患者中发生率更高的不良事件包括手足皮肤反应、脱发和皮疹。EORTC QLQ-C30(欧洲癌症研究与治疗组织生活质量问卷-核心36)身体和角色功能测定显示，两组患者12周时生活质量均下降，brivanib组的降低幅度更大，两组差异较小但有统计学意义，这一结果的临床意义尚不明确。

这项试验由brivanib的开发者百时美施贵宝公司资助。Johnson博士披露无相关利益冲突。

By: JEFF EVANS, Oncology Practice

BOSTON – The investigational antiangiogenic drug brivanib failed to achieve noninferiority to sorafenib in a phase III trial testing the two for first-line treatment of advanced hepatocellular carcinoma.

There is an unmet medical need for more effective and better tolerated drugs for the first-line treatment of advanced hepatocellular carcinoma (HCC) than sorafenib (Nexavar), the only drug approved by the Food and Drug Administration for the indication. In particular, in Asian-Pacific and sub-Saharan countries where HCC is most prevalent, "many patients have such advanced disease at diagnosis that potentially curative treatments are no longer available," Dr. Philip Johnson said at the annual meeting of the American Association for the Study of Liver Diseases.

He and his colleagues randomized 1,155 patients to double-blind treatment with either sorafenib, a multitargeted kinase inhibitor, or brivanib, a dual vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors inhibitor. Both receptors are known to play a role in tumor growth, survival, and metastasis through proangiogenic signaling in HCC tumor cells.

The patients in this multicenter study, who had not yet received any systemic therapy, had a mean age of about 60 years, and most were men (84%). About two-thirds of the patients were Asian, and 92% were in Child-Pugh class A. The groups had a similar prevalence of infection with hepatitis B (20%) or hepatitis C (45%) viruses and alcoholic liver disease (16%).

The trial, known as the BRISK-FL study, had a hybrid noninferiority/superiority design in which the investigators set a noninferiority upper margin of 1.08, which equates to no more than a 3-week difference in median overall survival. This ensured that the risk of dying while taking brivanib was not unacceptably higher than with sorafenib, explained Dr. Johnson, professor of oncology and translational research and director of the Cancer Research U.K. Clinical Trials Unit at the University of Birmingham in England.

Based on the sample size, a noninferiority upper margin of 1.08 meant that the estimated hazard rate had to be 0.94 at highest for brivanib to be considered noninferior to sorafenib. Comparisons of the median overall survival between the groups showed an overall hazard ratio of 1.07 for brivanib with an upper 95% confidence interval value of 1.23, which was higher than the predetermined limit for noninferiority of 1.08 or less.

Median overall survival was 9.9 months with sorafenib and 9.5 months with brivanib. No subgroup of patients had better survival with either drug. The median time-to-progression was nearly equal in patients treated with sorafenib (4.1 months) and brivanib (4.2 months). Rates of complete, partial, and overall response, as well as disease control, were all similar between the groups.

A 50% or greater reduction in the level of alpha-fetoprotein occurred in 31% of 270 patients taking sorafenib and in 58% of 250 patients taking brivanib. A decline in alpha-fetoprotein levels has been considered an indication of tumor cells killed, Dr. Johnson said.

Similar percentages of patients in each group had dose reductions or underwent poststudy treatments. Both groups had similar rates of study discontinuation; the most frequent reasons were disease progression and drug toxicity.

Both agents also had similar rates of overall adverse events, but brivanib-treated patients experienced significantly higher rates of decreased appetite, fatigue, hypertension, nausea, vomiting, and hyponatremia. The adverse events that occurred more often among sorafenib-treated patients included hand-foot skin reaction, alopecia, and rash.

Both groups showed declines in quality of life at 12 weeks on the physical and role functions measured by the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer’s Quality of Life Questionnaire–Core 36). Small, but statistically significantly greater declines in these functions in the brivanib arm have unknown clinical significance, Dr. Johnson said.