Avastin获批用于治疗胶质母细胞瘤

ST LOUIS (MD Consult) - On May 5, 2009, Genentech, Inc, announced that the US Food and Drug Administration (FDA) granted accelerated approval of Avastin (bevacizumab) for the treatment of glioblastoma in persons with progressive disease following prior therapy. The effectiveness of Avastin in this aggressive form of brain cancer was determined on the basis of an improvement in objective response rate observed in some clinical trials. However, no data are currently available from randomized controlled trials demonstrating an improvement in disease-related symptoms or increased survival with Avastin in glioblastoma. In the near future, Genentech expects to begin enrollment in a phase 3 trial for patients with newly diagnosed glioblastoma to further evaluate Avastin in this setting.

The accelerated FDA approval was granted on the basis of independently reviewed data from an open-label, multicenter, noncomparative phase 2 study that included 167 patients with glioblastoma whose cancer had progressed after initial treatment with temozolomide and radiation. Patients in the study were randomly assigned to 2 arms: Avastin alone or Avastin in combination with irinotecan. A primary end point of the study was objective response rate. Response was assessed using magnetic resonance imaging and measured using World Health Organization radiographic criteria along with decreased or stable corticosteroid use.

The median age of patients in this phase 2 study who were treated with Avastin alone was 54 years. Additionally, 32% were female, 81% were in first relapse, 45% had a Karnofsky performance status (KPS) score of 90 to 100, and 55% had a KPS score of 70 to 80. Patients with active brain hemorrhage were excluded from the study. In the trial, safety in this patient population was consistent with Avastin experience in other tumor types. According to an FDA analysis of the study, tumor responses were observed in 26% (95% confidence interval [CI],17.0%-36.1%) of the 85 patients treated with Avastin alone, and the median duration of response in these patients was 4.2 months (95% CI, 3.0-5.7 months).

The efficacy of Avastin in glioblastoma that has progressed following prior therapy is also supported by results from another study that used the same response assessment criteria as detailed for the previously mentioned study. In this single-arm study, 56 patients were treated with Avastin alone. Responses were observed in 20% of patients (95% CI, 10.9%-31.3%), and the median duration of response was 3.9 months (95% CI, 2.4-17.4 months). In this study, Avastin was discontinued as a result of adverse events in 5% of patients. The most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), diarrhea (21%), and epistaxis (19%). Two deaths occurred in the study.

Avastin is a biologic antibody designed to specifically inhibit the vascular endothelial growth factor (VEGF) protein that plays an important role in the development and maintenance of blood vessels, a process known as angiogenesis. Glioblastomas express high levels of VEGF and develop an extensive network of tumor blood vessels. VEGF is a potent activator of angiogenesis throughout the lifecycle of a tumor and is thought to be critical to a tumor's ability to grow and metastasize.

圣路易斯(MD Consult)——2009年5月5日，基因泰克公司宣布，美国食品药品管理局(FDA)同意加快批准Avastin(贝伐单抗)用于治疗在先前治疗后出现疾病进展的胶质母细胞瘤患者。一些临床试验中观察到客观有效率改善，由此证实Avastin对此侵袭性脑癌具有疗效。然而，目前尚无随机对照试验显示，应用Avastin治疗胶质母细胞瘤时可改善疾病相关症状或延长生存时间。 在不久的将来，基因泰克公司计划招募新确诊的胶质母细胞瘤患者进行3期试验，以进一步评估Avastin对此类患者的疗效。

FDA同意加快批准是基于一项开放标记、多中心、非对照2期研究的独立回顾数据。该研究纳入167例经替莫唑胺和放疗初步治疗后癌症出现进展的胶质母细胞瘤患者。患者被随机分入2组：Avastin单药治疗组和Avastin+伊立替康联合治疗组。该研究的主要终点是客观有效率。采用根据世界卫生组织放射学标准评判的磁共振成像及通过皮质类固醇使用量是否减少或稳定来评测疗效。

在该2期研究中，Avastin单药治疗组患者的平均年龄是54岁。此外，32%的患者为女性；81%患者为首次复发；45%患者 的卡诺夫斯基能力状态(KPS)评分为90~100分；55%患者的KPS评分为70~80分。该研究排除活动性脑出血的患者。Avastin在该患者人群中的安全性与在其他肿瘤类型患者人群中的安全性一致。FDA对该研究的分析显示，Avastin单药治疗组85例患者的肿瘤有效率为26%[95%可信区间(CI)，17.0%～36.1%]，平均有效持续时间为4.2个月(95%CI，3.0个月～5.7个月)。

另1项采用与上述研究相同的疗效评价标准的研究也证明，Avastin可有效治疗在先前治疗后出现进展的胶质母细胞瘤患者。在该单组研究中，56例患者接受Avastin单药治疗。治疗有效率为20%(95% CI，10.9%～31.3%)，平均有效持续时间为3.9个月(95% CI，2.4个月～17.4个月)。在该研究中，因不良事件所致Avastin停用率为5%。最常报告的不良事件是感染(55%)、疲劳(45%)、头痛(37%)、高血压(30%)、腹泻(21%)和鼻出血(19%)。 该研究中出现2例死亡。

Avastin是一种生物抗体，可特异性抑制血管内皮生长因子(VEGF)蛋白。VEGF蛋白对血管的形成和维持即血管生成过程起重要作用。胶质母细胞瘤表达高水平VEGF，并形成广泛肿瘤血管网络。VEGF是整个肿瘤生命周期中血管生成的有效激活因子，对肿瘤的生长和转移能力起关键作用。

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