CHICAGO (EGMN) – Bevacizumab, alone or in combination with irinotecan, is generally safe and active in patients with relapsed glioblastoma, according to updated results of the phase II BRAIN trial.

“Up to 16% of patients who received bevacizumab-based therapy remained alive at 30 months,” lead investigator Dr. Timothy Cloughesy reported at the annual meeting of the American Society of Clinical Oncology. “The incidence of selected [adverse events] in the updated safety data was consistent with what was previously reported – there were no new safety signals that were identified.”

The Study to Evaluate Bevacizumab Alone or in Combination With Irinotecan for Treatment of Glioblastoma Multiforme (BRAIN) trial’s efficacy results compare favorably with those of similar trials testing other regimens, according to Dr. Cloughesy: the 12-month survival rate was 38% with bevacizumab-based therapy, whereas it has been 14%-27% with cytotoxic agents such as temozolomide or lomustine.

Sorting out the specific contributions of bevacizumab and irinotecan to the observed outcomes is difficult because of the trial’s design, he said. However, “when we look at what is providing the majority of the effect that we are seeing, I think it is coming from bevacizumab.”

The multicenter trial, sponsored by Genentech (manufacturer of bevacizumab), opened in July 2006 to patients with glioblastoma in first or second relapse who had previously received radiation therapy and temozolomide.

They were randomly assigned in nearly equal numbers to open-label treatment with bevacizumab alone or bevacizumab plus irinotecan. Patients in the monotherapy group who experienced progression could then receive the combination on a postprogression phase of the trial.

Initial results, reported at the same meeting 2 years ago, were based on a data cutoff of September 2007, according to Dr. Cloughesy. Updated results were based on data cutoffs of July 2008 (treatment exposure, safety, and median survival) and July 2009 (survival rates).

The 167 enrolled patients had a median age of about 55 years. The majority were male (68%) and white (90%), and experiencing a first relapse (81%). Fifty-nine percent of the patients in the bevacizumab arm had progression, and went on to receive the combination therapy.

The median number of bevacizumab doses received was 9 in the bevacizumab group and 11 in the bevacizumab-irinotecan group during the main phase of the trial, reported Dr. Cloughesy, director of the neuron-oncology program and a clinical professor at the Ronald Regan UCLA Medical Center in Los Angeles. The median number was three during the post-progression phase.

The updated safety data showed little change from the initial results, he said. Some 51% of patients in the bevacizumab group and 71% in the bevacizumab-irinotecan group had adverse events of grade 3 or higher. Hypertension was the predominant event with monotherapy (11%), whereas venous thromboembolism was the predominant event with combination therapy (10%).

“The things that ... we are concerned about with regard to patients who are taking anti-VEGF [vascular endothelial growth factor] therapy – cerebral hemorrhage, wound healing, arterial thrombotic embolism, and gastrointestinal perforation – these all stayed fairly low,” he commented, occurring at a severity of grade 3 or higher in only 0%-3.6% of patients. “There was no significant change from the prior data that was presented.”

The median duration of overall survival was 9.3 months with bevacizumab alone and 8.9 months with bevacizumab-irinotecan. The percentage of patients still alive was 38% in each arm at 12 months; 24% and 18%, respectively, at 18 months; 16% and 17%, respectively, at 24 months; and 11% and 16%, respectively, at 30 months.

Commenting on the 30-month values, Dr. Cloughesy said, “I don’t think that’s a meaningful difference. We are getting down to very small numbers, and I can’t draw any conclusions from that.”

When efficacy results were compared with those of published, multicenter trials of other regimens in patients with relapsed glioblastoma that used central radiology and pathology review, the 12-month survival rate with bevacizumab-based therapy (38%) was higher than that seen with agents such as temozolomide and lomustine (14%-27%).

“Bevacizumab can be easily used with other chemotherapies,” noted Dr. Cloughesy. However, open-label, single-arm trials to date have not identified a combination superior to bevacizumab alone.

Dr. Alba A. Brandes, a medical oncologist at Azienda USL in Bologna, Italy, noted that the trial’s size and promising results were strengths, whereas its evaluation criteria and lack of a standard control arm and biomarker studies were weaknesses.

“Bevacizumab has brought light into the treatment of recurrent GBM [glioblastoma multiforme], a setting with scarce options and dismal results,” she commented.

“The advantage of bevacizumab over classical cytotoxics seems to be in the range of 2 to 3 months. That represents a prolongation of 30% in survival at recurrence,” said Dr. Brandes. “However, this advantage should be proven in phase III trials.”

Genentech sponsored the trial. Some of the investigators are employees of or consultants to Genentech, or have received honoraria or research funding from the company. Dr. Brandes disclosed having a consultant or advisory role with and receiving honoraria from Roche, which owns Genentech.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

芝加哥(EGMN)——据BRAIN Ⅱ期临床试验的最新结果，单独使用贝伐单抗或将其与伊立替康联合使用以治疗患有复发性胶质母细胞瘤的患者通常是安全有效的。

 

该试验的主要研究者Timothy Cloughesy博士在美国临床肿瘤学会年会上报告说：“接受贝伐单抗为主治疗的患者中多达16%的患者生存期超过30个月，最新安全数据显示，特定不良事件的发病率和既往研究报道的结果一致——我们并未发现新的安全信号。”

 

据Cloughesy博士介绍，该研究对单独使用贝伐单抗或联用伊立替康治疗多形性胶质母细胞瘤(BRAIN)试验的疗效结果进行了评估，该结果显示，与检测其他治疗方案的类似临床试验相比，该试验得出了更加肯定的结论。接受贝伐单抗为主治疗的患者12个月生存率为38%，然而，在使用细胞毒性药物(譬如替莫唑胺或洛莫司汀)对患者进行治疗时该数值仅为14%~27%。

 

他说，受限于该试验的研究设计，想要从观察结果中辨别贝伐单抗和伊立替康的具体贡献极为困难。然而，“当我们考虑究竟是何种药物提供了我们所观察到的疗效的主体时，我想这来自贝伐单抗。”

 

这一由基因泰克公司(贝伐单抗的制造商)赞助的多中心临床试验于2006年7月对胶质母细胞瘤首度或二度复发的患者开放，这些患者之前均曾接受过放射治疗和替莫唑胺。

 

他们被随机分配接受单独使用贝伐单抗或联用伊立替康的开放式治疗，每组患者人数近乎相等。接受单药治疗的患者如果出现病情进展，则在该试验的病情进展后阶段，安排其接受联合治疗。

 

据Cloughesy 博士介绍，2年前同一会议曾经报道了该研究的最初结果，该结果基于截至2007年9月的相关数据。最新的研究结果则基于截至2008年7月(治疗暴露、安全性和中位生存期)和2009年7月的数据。

 

该研究纳入的167例患者的中位年龄大约为55岁。其中大部分为男性(68%)和白种人(90%)，且其正处于疾病首度复发(81%)中。贝伐单抗组的患者中有59%出现了疾病进展，且其随后接受了联合治疗。

 

加州大学洛杉矶分校罗纳德里根医学中心神经元-肿瘤项目负责人、医学教授Cloughesy博士报告说，在该试验的主要阶段，贝伐单抗的中位给药剂量值在贝伐单抗组为9，在贝伐单抗-伊立替康组则为11。在病情进展后阶段该剂量的中位值为3。

 

他说，据最新的安全数据显示，该数值较最初的结果并未发生太大改变。在贝伐单抗组和贝伐单抗-伊立替康组大约分别有51%和71%的患者出现3级或3级以上不良事件。当对患者使用单药治疗时，高血压是最主要的事件(11%)，而在进行联合治疗时，静脉血栓栓塞是最主要的事件(10%)。

 

他评价说：“对于那些正接受抗血管内皮生长因子(VEGF)治疗的患者，我们担心的事情包括……脑出血、创伤修复、动脉血栓栓塞和胃肠道穿孔，但这些事件均维持了非常低的发病率” ，仅有0~3.6%的患者发生了3级或3级以上不良事件。“和以前提交的数据相比，该结果并未发生显著改变。”

 

单独使用贝伐单抗及联用贝伐单抗-伊立替康时，患者中位总体生存期分别为9.3个月和8.9个月。每组患者在第12个月的生存率均为38%；在第18个月则分别为24%和18%；在第24个月则分别为16%和17%；在第30个月则分别为11%和16%。

 

Cloughesy博士在对30个月的数值进行评论时说：“我不认为这是一个有意义的差异。我们获得了非常小的数值，所以我无法从中得出任何结论。”

 

当研究者将这一疗效结果与那些已发表的多中心临床试验结果进行对比时(这些试验采用其他方案对复发性胶质母细胞瘤患者进行治疗，且这些患者主要使用放射疗法和病理学检查)，他们发现，使用以贝伐单抗为主治疗的患者12个月生存率(38%)较使用替莫唑胺和洛莫司汀之类药物进行治疗所观察到的(14%~27%)高。

 

Cloughesy博士指出：“贝伐单抗无疑可与其他化疗药物联合使用” ，然而，开放性单组临床试验迄今尚未证实联合治疗的疗效优于贝伐单抗单药治疗。

 

意大利博洛尼亚市Azienda USL医院的肿瘤内科医生Alba A. Brandes博士指出，该研究的优势在于其样本量和令人充满希望的研究结果，而其缺点则在于其评估标准以及缺乏标准对照组和生物标志物相关研究。

 

她评论说：“贝伐单抗为复发性多形性胶质母细胞瘤(GBM)的治疗带来了希望，该病治疗方案稀缺且预后极差。”

 

Brandes博士说：“贝伐单抗相较于传统细胞毒药物的生存期优势大约在2~3个月范围内。那意味着其可以使患者复发后生存期延长30%，然而，这一优势须在III 期临床试验中予以验证。”

 

基因泰克公司是该试验的赞助方。某些研究者是基因泰克公司的雇员或顾问，或曾接受该公司的酬金或研究资金。Brandes博士披露说曾任罗氏公司顾问或咨询师一职，且还曾接受过该公司的酬金，罗氏公司是基因泰克公司的控股方。

 

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