SILVER SPRING, Maryland (EGMN)–The results of two phase II studies support accelerated approval of the anti-angiogenesis drug bevacizumab as a treatment for refractory glioblastoma multiforme, a U.S. federal advisory panel unanimously agreed at a March 31 meeting.

The U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) voted 10 to 0 that the objective responses seen in the studies were strong enough to serve as a surrogate that was “reasonably likely” to predict clinical benefit as a treatment for patients with previously treated glioblastoma. The responses were based on MRI changes in patients treated with bevacizumab.

Marketed by Genentech, Inc., bevacizumab is under accelerated review for approval in the United States as a single agent for the treatment of patients with previously treated glioblastoma. Initially approved in 2004 as a first-line treatment for metastatic colorectal cancer, bevacizumab is a recombinant humanized monoclonal antibody that inhibits the vascular endothelial growth factor (VEGF). This can reduce tumor vascularization as well as capillary permeability. Glioblastomas express high levels of VEGF, and develop an extensive network of tumor blood vessels.

Under the FDA’s accelerated review program, preliminary data that are considered likely to predict clinical benefit can be the basis of provisional approval of drugs for serious or life-threatening diseases, particularly when few treatment options are available. Currently, lomustine and carmustine—including carmustine as an adjunct to surgery—are approved for treating previously treated glioblastoma.

Genentech submitted data from two single-arm studies of patients with previously treated glioblastoma: a company-sponsored multicenter, open label phase II study of 167 patients (85 on bevacizumab alone and 82 on bevacizumab plus irinotecan), who had been treated with surgery, radiation, and temozolomide, and had relapsed for the first or second time; and a supportive study independently conducted and sponsored by the U.S. National Cancer Institute of 56 patients with recurrent high-grade gliomas, treated with bevacizumab alone.

One-half of patients were on corticosteroids at baseline in the Genentech study. In both studies, bevacizumab was administered every two weeks, by IV infusion at a dose of 10 mg/kg.

In the Genentech study, the primary endpoint, objective response, as determined by MRIs, was achieved by 25.9% of patients in the bevacizumab-only arm, with a median duration of response (a secondary endpoint) among responders of 4.2 months, according to the FDA analysis of the data.

Almost all (99%) patients in the bevacizumab-only arm had an adverse event: 26% had a serious adverse event

Almost 5% discontinued the drug because of an adverse event. Common adverse events affecting more than 20% of patients included fatigue (45%), headache (38%), and hypertension (30%). Epistaxis occurred in about 20% of patients in both treatment arms.

In both treatment arms combined, almost 40% of the patients had bleeding/hemorrhage and 5% had CNS hemorrhage, which were induced by bevacizumab. Other reported adverse events included wound healing complications (6%), venous thromboembolic event (8%), and arterial thromboembolic event (6%). Two deaths were considered possibly related to the drug: a case of neutropenic sepsis in a patient in the bevacizumab-only arm and a retroperitoneal hemorrhage in the combination arm.

In the NCI study, the objective response rate was 19.6%, with a median duration of response among responders of 3.9 months, according to the FDA.

There were no complete responses in either study.

Among the issues raised by FDA staff members at the meeting were the single-arm design of the studies and use of historical controls. In addition, the FDA has not used objective response as the basis of an accelerated approval for glioblastoma treatments.

Moreover, because bevacizumab neutralizes VEGF-induced vascular permeability and stabilizes the blood-brain barrier, it reduces extravasation of fluid into the brain—reducing edema and the need for corticosteroids. Therefore, the FDA staff held that it is unclear whether improvements in MRIs associated with a reduced need for steroids could be due to the drug’s effect on the tumor, or represented a reduction in edema and/or radiation-induced necrosis.

Several ODAC panelists said a reduction in steroids was a meaningful improvement because of the adverse effects of steroids.

The acting chair of the panel, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, metabolism branch, at NCI’s Center for Cancer Research, said that he considered a response rate of 20% to 25% to be “very robust,” and that “the totality of data raised a reasonable likelihood of clinical benefit.”

Dr. Jay Loeffler, chair of the department of radiation oncology, Massachusetts General Hospital, Boston, said that the drug “represents a new generation of molecules to treat our patients with brain tumors,” and that he believed that benefit would be increased when the drug is used with radiation and chemotherapy in the initial treatment of glioblastomas.

He was among the several panel members who said they thought a large phase III trial, planned by Genentech and combining bevacizumab with radiation therapy and temozolomide in newly diagnosed patients with glioblastoma, would be positive.

For accelerated drug approvals, the company must confirm the benefits in a trial after approval.

Bevacizumab is approved in the United States for first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-flourouracil-based chemotherapy and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic, nonsquamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. It also received accelerated approval for treatment in combination with paclitaxel of metastatic HER2-negative breast cancer in patients not previously treated with chemotherapy.

The company expects the FDA to make a decision on approval by May 5.

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

马里兰州银泉(EGMN)——两项II期临床研究的报告支持抗血管生成药物贝伐单抗用于治疗多形性恶性胶质瘤，在3月31日的会议上，一个联邦专家顾问小组一致同意这一观点。

 

食品与药品管理局(FDA)的肿瘤药物咨询委员会(ODAC)以10:0的投票支持该研究，他们认为该研究有足够的事实依据，证明其可以作为过去曾经接受过治疗的多形性恶性胶质瘤患者的一种“合理的”替代治疗方法，可以预期患者能从该治疗当中获益。药物疗效的评估是根据患者使用贝伐单抗治疗以后的磁共振改变得出的。

 

基因泰克公司推出阿伐他汀后，单独使用贝伐单抗治疗曾经治疗过的恶性胶质瘤的证据的回顾性研究正不断增多。贝伐单抗是一种重组人类单克隆抗体，它可以抑制血管内皮生长因子(VEGF)，因此可以减少肿瘤血管生成以及血管通透性，于2004年最早被许可用于转移性结直肠癌的一线治疗。而恶性胶质瘤VEGF的表达水平很高，并可通过一系列的网络作用促进肿瘤血管生成。

 

在FDA的快速评估计划中，可让患者临床受益的药物的初期数据，可以作为暂时同意这些药物用于治疗严重的或者危及生命的疾病的依据，特别是当用于治疗这些疾病的方法非常少的时候。目前，作为手术的辅助治疗，环己亚硝脲和亚硝脲氮芥包括卡氮芥糯米纸胶囊剂(亚硝脲氮芥)都被许可用于曾经治疗过的恶性胶质瘤。

 

基因泰克公司牵头对过去进行过治疗的恶性胶质瘤的患者进行了两项研究，并对数据进行了总结：一项由多家公司资助的多中心开放性二期临床试验研究，共入选167例患者(85例只用贝伐单抗，82例使用贝伐单抗加伊立替康)，这些患者都接受过手术治疗、放疗以及替莫唑胺治疗，并且为第一次或者再次复发的患者；另外一项由国家癌症研究所(NCI)指导和资助的研究中，有56名复发的晚期神经胶质瘤患者参加，他们仅接受贝伐单抗治疗。

 

在基因泰克的研究中，一半的患者皮质类固醇处于基线水平。在这两项研究中，贝伐单抗都是每两周静脉注射一次，剂量为10 mg/kg体重。

 

FDA对试验数据分析发现，在基因泰克研究中，主要终点，即根据MRI结果体现的客观反应率，占所有单用贝伐单抗患者的25.9%，出现反应(次要终点)的中位数时间是4.2个月。

 

几乎所有患者(99%)在单独使用贝伐单抗后都出现了副作用，26%的患者出现了严重的副作用。

 

将近15%患者因为不能耐受副作用而停用了药物。最常见的副作用包括疲劳(45%)、头痛(38%)和高血压(30%)。两项试验中鼻出血的发生率几乎都是20%。

 

两项研究综合起来看，40%的患者出现了出血并发症，5%的患者出现了中枢神经系统出血，这些出血都是由贝伐单抗引起的。其他报道的副作用还包括伤口愈合困难(6%)。有两例患者死亡，并考虑其死亡与用药有关：一例是仅用贝伐单抗的患者出现了中性粒细胞减少的败血症，而在另外的一项研究中的一名患者出现了腹膜后出血。

 

根据FDA的分析，在NCI研究中，客观反应率为19.6%，中期反应时间为3.9个月。

 

两项研究都未曾出现完全的反应。

 

FDA专家提供的证据包括两项单方研究的结果和历史对照。另外，他们没有把对药物的客观反应性作为快速批准其治疗恶性胶质瘤的依据。

 

此外，由于贝伐单抗抑制了VEGF诱导的血管通透性增加，从而起到了稳定血脑屏障的作用，减少了液体向脑内的渗出，减轻脑水肿并且降低了对激素的需求。因此，FDA专家指出，头颅磁共振检查结果的改善以及患者对甾体类激素需要量的降低，不能完全归因于药物对肿瘤或水肿以及放射性坏死的治疗作用。

 

几名ODAC专家指出，由于甾体类激素本身的副作用，患者对甾体类激素需要量的降低本身就是一个很有意义的进步。

 

专家小组的执行主席，国家癌症研究所癌症研究中心淋巴瘤和代谢病病区的主任Wyndham Wilson医生说，他认为，20%到25%的有效率是“效果显著”的，“总的数据提示这些治疗有明确的临床疗效。”

 

波士顿的马萨诸塞州总医院肿瘤放射科主任Jay Loeffler医生说，这种药物“代表了治疗脑肿瘤的新一代药物，”并且他相信，这些药物对于初期已经给予放疗或化疗的恶性胶质瘤患者而言，疗效会更好。

 

他和小组的另外几位专家都认为，由基因泰克公司计划的，联合使用贝伐单抗、放疗和替莫唑胺，用来治疗新确诊的恶性胶质瘤患者的大型III期临床试验是可行的。

 

对于快速药物批准，公司必须在得到批准后再对该药进行试验以确认疗效。

 

贝伐单抗被批准与5-氟尿嘧啶联合使用，作为治疗转移性结直肠癌的一线和二线治疗手段；对于不能切除的、局部晚期的、复发或者转移的非鳞状细胞、非小细胞肺癌(NSCLC)，可联合卡铂和紫杉醇作为一线治疗药物。此外，贝伐单抗还被批准联合紫杉醇治疗过去未曾给予化疗的转移性HER2阴性的乳腺癌患者。

 

该公司期待可以在5月5日之前获得FDA的批准。