Knox Jennifer J, Qin Rui, Strosberg Jonathan R, Tan Benjamin, Kaubisch Andreas, El-Khoueiry Anthony B, Bekaii-Saab Tanios S, Rousey Steven R, Chen Helen X, Erlichman Charles
Staff Medical Oncologist, Gastrointestinal Oncology Lead, Princess Margaret Cancer Centre, University of Toronto, 5-210, 610 University Ave, Toronto, ON, M5G 2 M9, USA,
Invest New Drugs. 2015 Feb;33(1):241-6. doi: 10.1007/s10637-014-0169-3. Epub 2014 Oct 16.
There is strong rationale to combine temsirolimus (TEM) with Bevacizumab (BEV) for patients with advanced HCC.
A modified two-stage Simon phase II trial was performed with plans to advance to stage 2 if more than 2 patients had confirmed PR or >18 patients were progression free at 6 months out of 25 in stage 1. Toxicity, PFS and overall survival were secondary endpoints. Eligible pts had advanced HCC, Child Pugh A liver status and no prior systemic therapy involving the VEGF or m-TOR targeted agents. Patients were treated with temsirolimus 25 mg IV on Days 1, 8, 15, and 22 of a 28 day cycle and bevacizumab 10 mg/kg IV on Days 1 and 15 of the cycle.
Twenty-eight eligible patients were enrolled, 26 evaluable receiving a median of 6.5 cycles (range 1-18). Drug related toxicities were common including cytopenias, fatigue, mucositis, diarrhea and mild bleeds. Dose reductions or discontinuation of TEM were common. Accrual closed for presumed futility after interim analysis of the first 25 evaluable patients showed only one PR and 16/25 were progression-free at 6 months. However, the final data update in March 2013 demonstrated 4 confirmed PRs, a 5th unconfirmed PR and 16 /26 progression-free at 6 months. Median PFS and OS were 7 and 14 months respectively.
This first-line HCC trial evaluating the BEV/TEM doublet reports an ORR of 19 % and OS of 14 months which is favorable but requires further study at a more optimized dose and schedule.
对于晚期肝细胞癌（HCC）患者，将替西罗莫司（TEM）与贝伐单抗（BEV）联合使用有充分的理论依据。
进行了一项改良的两阶段西蒙二期试验，计划如果在第一阶段的25名患者中有超过2名患者确认部分缓解（PR）或>18名患者在6个月时无进展，则进入第二阶段。毒性、无进展生存期（PFS）和总生存期为次要终点。符合条件的患者患有晚期HCC，肝功能为Child Pugh A级，且既往未接受过涉及血管内皮生长因子（VEGF）或雷帕霉素靶蛋白（m-TOR）靶向药物的全身治疗。患者在28天周期的第1、8、15和22天接受静脉注射替西罗莫司25mg，并在周期的第1天和第15天接受静脉注射贝伐单抗10mg/kg。
招募了28名符合条件的患者，26名可评估患者接受的中位周期数为6.5个周期（范围1-18）。药物相关毒性常见，包括血细胞减少、疲劳、粘膜炎、腹泻和轻度出血。替西罗莫司的剂量减少或停药很常见。在对前25名可评估患者进行中期分析显示仅1例PR且16/25在6个月时无进展后，由于认为无效而停止入组。然而，2013年3月的最终数据更新显示有4例确认的PR，第5例未确认的PR以及16/26在6个月时无进展。中位PFS和总生存期（OS）分别为7个月和14个月。
这项评估BEV/TEM双联疗法的一线HCC试验报告的客观缓解率（ORR）为19%，OS为14个月，这是有利的，但需要在更优化的剂量和方案下进一步研究。
