Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial
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DOI：
10.1016/s0140-6736(07)61904-7
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发表时间：
2007-12-01
期刊：
影响因子：
168.9
通讯作者：
Moore, Nicola
中科院分区：
文献类型：
--
作者：
Escudier, Bernard;Pluzanska, Anna;Moore, Nicola
血管内皮生长因子（VEGF）抑制是治疗肾细胞癌的有效方法。因此，对人源化抗vegf单克隆抗体贝伐单抗与α干扰素联合治疗的研究是必要的。方法在一项多中心、随机、双盲、III期试验中，649例先前未经治疗的转移性肾细胞癌患者被随机分组，接受干扰素α -2a （9 MIU，每周皮下注射3次）和贝伐单抗（10 mg/kg，每2周；n=327）或安慰剂和干扰素α -2a （n=322）治疗。主要终点是总生存期。次要终点包括无进展生存期和安全性。在250例死亡后预先确定了总生存期的中期分析。在试验进行过程中出现了新的二线治疗方法，这可能会混淆总体生存数据的分析，我们同意监管机构的意见，即预先计划的无进展生存期最终分析可以接受监管提交。该方案被修改，允许在这一点上进行非盲法研究。无进展生存期的最终分析报告在此。按意向治疗进行疗效分析。宜必思试验已在centerwatch.com注册，编号BO017705E。结果：贝伐单抗加α干扰素组的325例患者和安慰剂加α干扰素组的316例患者接受了至少一次剂量的研究治疗。在解盲时，贝伐单抗加干扰素α组发生了230例进展事件，对照组发生了275例；贝伐单抗加干扰素组有114例死亡，对照组有137例死亡。贝伐单抗联合干扰素α组的中位无进展生存期明显长于对照组(10。2个月vs 5.4个月；HR 0.63, 95% Cl 0.52-0.75；p = 0.0001)。无论风险组或是否接受减少剂量的α干扰素，贝伐单抗加α干扰素均可增加无进展生存期。8例（2%）接受一次或多次贝伐单抗治疗的患者和7例（2%）未接受贝伐单抗治疗的患者因不良事件死亡。研究人员认为，贝伐单抗组中只有3例死亡可能与贝伐单抗有关。最常见的3级或更严重的不良事件是疲劳（贝伐单抗组40例[12%]对对照组25例[8%]）和虚弱（34例[10%]对20例[7%]）。与单用干扰素相比，贝伐单抗联合干扰素作为转移性肾细胞癌患者的一线治疗可显著改善无进展生存期。
Background Vascular endothelial growth factor (VEGF) inhibition is a valid therapeutic approach in renal cell carcinoma. Therefore, an investigation of the combination treatment of the humanised anti-VEGF monoclonal antibody bevacizumab with interferon alfa was warranted.Methods In a multicentre, randomised, double-blind, phase III trial, 649 patients with previously untreated metastatic renal cell carcinoma were randomised to receive interferon alfa-2a (9 MIU subcutaneously three times weekly) and bevacizumab (10 mg/kg every 2 weeks; n=327) or placebo and interferon alfa-2a (n=322). The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. An interim analysis of overall survival was prespecified after 250 deaths. On the basis of new second-fine therapies that became available while the trial was in progress, which could have confounded analyses of overall survival data, we agreed with regulatory agencies that the pre-planned final analysis of progression-free survival would be acceptable for regulatory submission. The protocol was amended to allow the study to be unblinded at this point. The final analysis of progression-free survival is reported here. Efficacy analyses were done by intention to treat. Ibis trial is registered with centerwatch.com, number BO017705E.Findings 325 patients in the bevacizumab plus interferon alfa group and 316 in the placebo plus interferon alfa group received at least one dose of study treatment. At the time of unblinding, 230 progression events had occurred in the bevacizumab plus interferon alfa group and 275 in the control group; there were 114 deaths in the bevacizumab plus interferon alfa group and 137 in the control group. Median duration of progression-free survival was significantly longer in the bevacizumab plus interferon alfa group than it was in the control group (10 . 2 months vs 5.4 months; HR 0.63, 95% Cl 0.52-0.75; p=0.0001). Increases in progression-free survival were seen with bevacizumab plus interferon alfa irrespective of risk group or whether reduced-dose interferon alfa was received. Deaths due to adverse events were reported in eight (2%) patients who received one or more doses of bevacizumab and seven (2%) of those who did not receive the drug. Only three deaths in the bevacizumab arm were considered by investigators to be possibly related to bevacizumab. The most commonly reported grade 3 or worse adverse events were fatigue (40 [12%] patients in the bevacizumab group vs 25 [8%] in the control group) and asthenia (34 [10%] vs 20 [7%]).Interpretation The combination of bevacizumab with interferon alfa as first-line treatment in patients with metastatic renal cell carcinoma results in a significant improvement in progression-free survival, compared with interferon alfa alone.