Lessons learned: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2.
Background: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC).
Methods: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2.
Results: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts.
Conclusion: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.
经验总结
•采用与经典的索拉非尼抗血管内皮生长因子抑制作用不同的抗血管生成机制的Trebananib治疗晚期肝细胞癌（HCC）患者未发现4个月时无进展生存率有改善。
•为支持既往报告的高Ang‐2水平与HCC患者不良结局的关联, Trebananib治疗和研究入组时较低水平的基线Ang‐2与总生存期改善至22个月有关, 提示未来的研究需要在低基线Ang‐2背景下进行。
摘要
背景. Ang‐1和Ang‐2属于血管生成素, 被认为通过活化Tie‐2血管生成素受体促进新血管形成。 Trebananib阻断Ang‐1和Ang‐2, 从而阻止其与Tie‐2受体的相互作用。 Trebananib联合索拉非尼组合的毒性可接受。Ang‐2水平升高与肝细胞癌（HCC）的预后不佳有关。
方法.东部肿瘤协作组评分≤2和Childs‐Pugh A级的HCC患者接受了Trebananib (10mg/kg 或15mg/kg, IV, 每周一次）联合索拉非尼（400mg, 口服, 每天两次）的给药。相对于索拉非尼历史对照的62％（把握度= 80％, α= 0.20）, 本研究计划使无进展生存（PFS）率在4个月时达到≥78％。次要终点包括安全性、耐受性、总生存期（OS）和多种生物标志物（包括血清Ang‐2）。
结果.依次将三十名患者入组到两个非随机分配的队列中。两组和历史对照之间的人口统计学相当。10mg/kg 和15mg/kg Trebananib队列4个月时的PFS率分别是57% 和 54%, 中位OS分别为17个月和11个月。在≥10％的患者中观察到3级及以上事件, 包括疲劳、高血压、腹泻、肝衰竭、掌足癣红斑综合征、呼吸困难和低磷血症。一名患者因肝衰竭死亡。中位血清Ang‐2与两个队列中的OS改善有关。
结论.与索拉非尼历史对照相比, 任何一个队列中4个月时的PFS率都没有得到改善。
Trial registration: ClinicalTrials.gov NCT00872014.
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