Escudier Bernard, Pluzanska Anna, Koralewski Piotr, Ravaud Alain, Bracarda Sergio, Szczylik Cezary, Chevreau Christine, Filipek Marek, Melichar Bohuslav, Bajetta Emilio, Gorbunova Vera, Bay Jacques-Olivier, Bodrogi Istvan, Jagiello-Gruszfeld Agnieszka, Moore Nicola
Department of Medicine, Institut Gustave Roussy, Villejuif, France.
Lancet. 2007 Dec 22;370(9605):2103-11. doi: 10.1016/S0140-6736(07)61904-7.
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.
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-line 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. This trial is registered with centerwatch.com, number BO17705E.
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% CI 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%]).
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.
血管内皮生长因子（VEGF）抑制是肾细胞癌的一种有效治疗方法。因此，有必要研究人源化抗VEGF单克隆抗体贝伐单抗与干扰素α的联合治疗。
在一项多中心、随机、双盲、III期试验中，649例既往未接受过治疗的转移性肾细胞癌患者被随机分为两组，分别接受干扰素α-2a（9 MIU皮下注射，每周3次）和贝伐单抗（10 mg/kg，每2周1次；n = 327），或安慰剂和干扰素α-2a（n = 322）。主要终点为总生存期。次要终点包括无进展生存期和安全性。在250例死亡病例出现后预先设定了总生存期的期中分析。由于在试验进行期间出现了新的二线治疗方法，这可能会混淆总生存期数据的分析，我们与监管机构达成一致，认为无进展生存期的预先计划最终分析可用于监管申报。方案进行了修订，以便在此阶段对研究进行揭盲。此处报告无进展生存期的最终分析。疗效分析采用意向性治疗。该试验已在centerwatch.com注册，编号为BO17705E。
贝伐单抗加干扰素α组325例患者和安慰剂加干扰素α组316例患者接受了至少一剂研究治疗。在揭盲时，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α组有114例死亡，对照组有137例死亡。贝伐单抗加干扰素α组的无进展生存期的中位数明显长于对照组（10.2个月对5.4个月；HR 0.63，95%CI 0.52 - 0.75；p = 0.0001）。无论风险组如何或是否接受减量干扰素α，贝伐单抗加干扰素α均可使无进展生存期延长。接受一剂或多剂贝伐单抗的患者中有8例（2%）报告因不良事件死亡，未接受该药物的患者中有7例（2%）。研究者认为贝伐单抗组只有3例死亡可能与贝伐单抗有关。最常报告的3级或更严重不良事件为疲劳（贝伐单抗组40例[12%]患者对对照组25例[8%]患者）和乏力（34例[10%]对20例[7%]）。
与单独使用干扰素α相比，贝伐单抗与干扰素α联合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。
