CHICAGO (EGMN) – A new protocol that adds temozolomide and radiation to bevacizumab and irinotecan for patients with newly diagnosed glioblastoma multiforme has resulted in a median overall survival that reached 21.2 months, according to a poster from Duke University Medical Center.
At 16 months, 65.3% of the first 75 patients in the up-front, phase II trial were still alive, investigators reported at the annual meeting of the American Society of Clinical Oncology. The 2-year overall survival rate was 45%.
“We were not surprised by the findings. ... We had shown that bevacizumab plus irinotecan had good efficacy in glioblastoma,” said principal investigator Dr. James Vredenburgh, a professor of medicine and the medical director of adult clinical services at Duke.
In May 2009, the U.S. Food and Drug Administration granted accelerated approval to second-line bevacizumab monotherapy for treatment of glioblastoma that had progressed after first-line treatment. Temozolomide was approved in March 2005 as a first-line treatment with radiation and as a maintenance therapy.
The new experimental protocol uses bevacizumab in combination with temozolomide and radiation therapy, followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma multiforme and gliosarcoma.
The study rationale was that VEGF (vascular endothelial growth factor) is an essential part of glioblastoma biology, and the anti-VEGF monoclonal antibody bevacizumab has demonstrated synergy with radiation and chemotherapy. Irinotecan was thought possibly to have synergy with temozolomide. Bevacizumab with or without irinotecan had shown activity in recurrent disease. Finally, it was thought that survival might be improved by including bevacizumab with chemotherapy in newly diagnosed patients.
Using previously reported median survival of 15.8 months in resected patients (N. Engl. J. Med. 2005;352:987-96) as a benchmark, the investigators set the primary end point of this trial as the proportion of patients who were alive 16 months after initiation of combination chemoradiotherapy, with a target of more than 60%.
The study was opened on August 15, 2007, and 75 patients were accrued through September 4, 2008, with a median follow-up of 25 months (range, 19-31 months). A second cohort of 50 patients was enrolled from October 30, 2008, to March 26, 2009, to investigate the DNA-repair gene MGMT and biomarkers. These 50 patients are included in the toxicity data, but not in the survival analysis.
The protocol called for all patients to start receiving radiation therapy and temozolomide at 75 mg/m2 per day at 2-6 weeks post craniotomy. They began bevacizumab 10 mg/kg every 14 days at least 4 weeks after surgery. After radiation therapy, patients received 6-12 monthly cycles of temozolomide at 200 mg/m2 per day on days 1-5, bevacizumab at 10 mg/kg, and irinotecan (340 mg/m2 for patients on enzyme-inducing antiepileptic drugs [EIAEDs] and at 125 mg/m2 for patients not on EIAEDs) on days 1 and 15.
Median progression-free survival reached 14.2 months, and the 2-year progression-free survival rate was 13.3% for the first 75 patients, Dr. Vredenburgh reported. Median overall survival from progression, which was measured in 62 patients, was 5 months; the 2-year overall survival from progression was 8.8%.
Grade 4 hematologic toxicity occurred in 17 of 125 patients, and deep vein thrombosis/pulmonary embolism occurred in 9 patients. All other toxicities occurred in not more than two patients. There were four toxic deaths (one each from myocardial infarction, DVT/PE, sepsis, and pneumocystis pneumonia).
Asked about the next step, Dr. Vredenburgh said, “[If] you do a phase II, you always need a phase III to confirm it.”
Two pivotal phase III, placebo-controlled studies are underway. These are studies of standard temozolomide and radiation plus or minus bevacizumab, followed by 6-12 months of temozolomide plus or minus bevacizumab, in patients with newly-diagnosed GBM. One trial, a RTOG (Radiation Therapy Oncology Group) study, stratifies patients by MGMT methylation status and molecular profile. The second study, by Roche, (parent company of Genentech Inc., the U.S. developer of bevacizumab), stratifies patients by country and recursive partitioning analysis.
“I think that these findings will encourage investigators to enroll patients on the phase III studies, and I think the phase III studies will change clinical practice,” said Dr. Vredenburgh.
The investigators concluded, among other things, that VEGF is pivotal in glioblastoma biology, and that understanding the mechanisms of VEGF resistance will be necessary to further improve survival. This point was taken up by discussant Dr. Michael D. Prados, director of translational research in neuro-oncology at the University of California, San Francisco, as he reviewed six papers, many examining the action of VEGF inhibition in glioblastoma.
“The theme of these posters is angiogenesis ... but the other theme is end points,” said Dr. Prados. “How do we get from A to B? How do we understand A to B?” He presented A to B as a continuum from diagnosis to treatment, relapse, salvage, and cure.
Many posters at ASCO use terms such as “progression-free survival,” he said, and they illustrate this with slides, while in fact having somewhat different definitions of both the term and the proof. He asked the audience to consider, for example, the meaning of progression. Dr. Prados concluded that biomarker validation is important, and quoted another speaker who had said that “tissue is the issue.” Tissue correlates are essential for accurate diagnosis of a drug’s efficacy, said Dr. Prados.
He also reflected on the ability of anti-VEGF therapy to give rise to re-neovascularization, and to create an invasive phenotype. He encouraged the audience to think about the ways in which glioblastomas might overcome the growth restrictions imposed by antiangiogenic agents.
The investigator-sponsored study received support from Genentech Inc. and Schering-Plough. Dr. Vredenburgh said he consults for Genentech. Dr. Prados disclosed research funding from Exelixis Inc., Genentech, Roche, and Schering-Plough.
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芝加哥(EGMN)——据杜克大学医学中心的一份壁报，贝伐单抗联合伊立替康辅以替莫唑胺加化疗，使新诊断的多形性胶质母细胞瘤(GBM)患者的中位总体生存期达到21.2个月。
研究者在美国临床肿瘤学会(ASCO)年会上报告指出，在16个月时，前导性II期临床试验中前75例患者中有65.3%仍存活。2年总生存率为45%。
主要研究者、杜克大学成人临床服务中心医学教授及医学主任James Vredenburgh博士说：“我们对结果并不感到意外……我们已经提出贝伐单抗加伊立替康治疗对胶质母细胞瘤有良好疗效。”。
2009年5月，美国食品药品管理局(FDA)通过快速审批程序批准了二线贝伐单抗单药化疗作为经一线治疗后病情进展的胶质母细胞瘤的治疗方案。替莫唑胺于2005年3月获准联合放疗作为一线治疗药及作为维持治疗药。
新的试验性治疗方案将贝伐单抗联合替莫唑胺和放疗，继之以贝伐单抗、替莫唑胺和伊立替康，作为新诊断的多形性胶质母细胞瘤和胶质肉瘤患者的治疗方案。
该研究的依据为血管内皮生长因子(VEGF)是胶质母细胞瘤的生物学基础，抗VEGF单克隆抗体贝伐单抗已证实与放疗和化疗具有协同作用。有人认为，伊立替康可能与替莫唑胺有协同作用。贝伐单抗联用或不联用伊立替康在复发性疾病治疗中均显示出了疗效。最后一点，据认为，对新诊断的患者采用贝伐单抗联合化疗可能会改善其生存状况。
以之前报道的行手术切除术的患者15.8个月的中位生存期为基准(N. Engl. J. Med. 2005;352:987-96)，研究者将本试验的主要终点设定为放化疗联合治疗方案开始后16个月存活的患者比例，目标为60%以上。
研究启动日期为2007年8月15日，截至2008年9月4日共募集了75例患者，中位随访时间为25个月(19~31个月)。另一个由50例患者构成的队列是在2008年10月30日至2009年3月26日期间募集的，其目的为研究DNA修复基因MGMT和生物标志物。这50例患者均被纳入毒性分析数据中，但未包括在生存分析中。
研究方案要求所有患者在开颅术后2~6周开始接受放疗联合替莫唑胺(剂量为75 mg/m2/d)化疗。从术后至少4周开始，这些患者每14天服用1次贝伐单抗，剂量为10 mg/kg。在放疗后，患者接受以1个月为1个疗程的替莫唑胺、贝伐单抗和伊立替康联合治疗，共进行6~12个疗程，具体方案如下：第1~5天每天服用替莫唑胺200 mg/m2，第1天和第15天给予服用贝伐单抗10 mg/kg和伊立替康治疗，其中，接受酶诱导性抗癫痫药物(EIAED)治疗的患者伊立替康的剂量为340 mg/m2，而未接受EIAED治疗者伊立替康的剂量为125 mg/m2。
Vredenburgh博士报告指出，前75例患者的中位无进展生存生存期达到14.2个月，2年无进展生存率为13.3%。对62例患者的研究结果显示，进展后的中位生存期为5个月，进展后2年总生存率为8.8%。
125例患者中有17例出现4级血液学不良反应，9例患者发生深静脉血栓 (DVT)或肺栓塞(PE)。其他所有毒性表现的发生例数不超过2例。出现4例中毒死亡事件(分别死于心肌梗死、DVT或PE、脓毒血症以及肺囊虫肺炎)。
问及下一步工作时， Vredenburgh博士说： “你若做II期试验，则常常需要做III期试验对II试验进行验证。”
两项关键性III期、安慰剂对照研究已在进行中，探讨标准的替莫唑胺与放疗联合或不联合贝伐单抗、继之以替莫唑胺联合或不联合贝伐单抗治疗，对新诊断的GBM患者的疗效。一项试验为RTOG(放射治疗肿瘤学组)研究，按照MGMT甲基化状态和分子谱对患者进行分层。另一项研究由罗氏(基因泰克公司的母公司，即美国贝伐单抗的研发厂家)进行，按照地区和递归分区分析对患者进行分层。
Vredenburgh博士说，“我认为，这些结果会鼓励研究者招募III期研究的受试者，我想III期研究将改变临床实践操作。”
研究者断言道，在其他生物标志物之中，VEGF在胶质母细胞瘤生物学中很关键，了解VEGF耐药性的产生机制是进一步改善患者生存状况的必要条件。讨论者、旧金山加州大学神经肿瘤学转化研究主任Michael D. Prados博士采纳了这一观点，他在对6篇论文进行综述时，主要探讨了胶质母细胞瘤中VEGF的抑制作用。
“这些壁报的主题是血管生成……但其他主题是终点事件”Prados博士说。“我们如何从A推导至B？我们如何理解A至B？”他在将A至B表示为由诊断至治疗、复发、抢救和治愈这一连续性过程。
他说，ASCO的许多壁报使用“无进展生存”这类术语，他们用幻灯片加以说明，然而实际上他们对术语和证据的定义均存在略微差别。例如，Prados博士要求听众斟酌进展的含义。他推断说，生物标志物的有效性很重要，同时还引用了另一位发言人所说的“tissue is the issue(组织是关键问题)”。组织病理学是精确诊断药物疗效的基本条件，Prados博士说。
他还反映了抗VEGF治疗引起新生血管化及产生浸润性表型的能力，并鼓励听众思考胶质母细胞瘤克制抗血管生成药物施加的生长限制的方式。
这项研究者发起的研究得到基因泰克公司和先灵葆雅公司的资助。Vredenburgh博士称其担任基因泰克公司的顾问。Prados博士披露获得Exelixis、基因泰克以及先灵葆雅公司的研究基金。
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