Everolimus延长了转移肾脏癌的无恶化存活

　　June 1, 2008 (芝加哥) —研究人员在美国临床肿瘤医学会第44届年会中发表指出，转移肾细胞癌(RCC)病患接受everolimus (RAD001)，相较于接受标准照护者，有明显较佳的无恶化存活；在6月时，使用everolimus治疗的病患中，有26%的RCC没有恶化；接受安慰剂者中，只有2%的RCC没有恶化；Everolimus组的平均无恶化存活4个月，安慰剂组为1.9个月
　　
　　主要作者、纽约Sloan-Kettering纪念癌症中心总医师Robert J. Motzer表示，过去几年，肾细胞癌的治疗方式有很的改变，因为对其生物学知识和标靶治疗的发展有长足进步；使用sunitinib或者sorafenib治疗已经成为标准照护。
　　
　　不过，使用sunitinib或者sorafenib治疗的病患还是有疾病恶化的可能，因此需要有效的治疗；Motzer医师表示，目还不符所需，有时候，病患对这些制剂发生阻抗性。
　　
　　Everolimus是天然巨环内脂sirolimus的衍生物，具有免疫抑制和抗血管新生两种性质，其目标在于细胞蛋白质mTOR，与异常生长、增生、癌症细胞存活等讯息路径有关的调节子，除了RCC，它可以用来评估许癌症的治疗，包括淋巴瘤和神经内分泌瘤。
　　
　　Everolimus在一个单组第二期转移RCC治疗前病患的试验中，显示出抗肿瘤活性；目前的是第三期研究，有410名转移RCC病患，在之前的治疗之后恶化；Motzer医师表示，本研究是全球性的，它是主要的治疗前组，许多病患接受过二或三种治疗。
　　
　　病患随机接受everolimus(272 人)或者最佳的支持照护(138 人)，所有的病患之前都曾以其他制剂治疗：71%使用sunitinib、55%使用 sorafenib、26%使用sunitinib和sorafenib；初级终点是无恶化存活，由独立访谈确认。
　　
　　Motzer医师表示，不是整体存活，因为考量到病患，我们希望有交叉时间点。
　　
　　目前已经计划最后的分析，但是第二次的期中分析显示，服用everolimus的病患有相当大的好处；Everolimus组减少了70%的癌症恶化，风险比只有0.30；测定这点时，独立的监测委员会建议研究可以停止；研究在停止时并未整合，和everolimus比对，服用安慰剂的病患有81%出现疾病恶化。
　　
　　此药物耐受不错，服用everolimus者有10%有需要停药的严重不良反应，安慰剂组有4%；因为不良反应需要减低剂量者，服用everolimus组有4%，安慰剂组不到1%。
　　
　　Everolimus最常见的不良反应 研究组 口腔炎 贫血事件 无力 治疗 各种等级 36% 28% 28% 等级 3 或 4 4% 7% 2% 安慰剂 各种等级 7% 15% 20% 等级 3 或 4 0% 5% 4%
　　Motzer医师结论表示，转移肾细胞癌病患在使用sunitinib和 sorafenib之后恶化，服用Everolimus可以延长无恶化存活；这是在sunitinib和sorafenib无效之后，首次且唯一有确立临床效果的制剂，应透过当局的核准，作为标准照护。
　　
　　未参与此研究的克里夫兰Taussig临床癌症中心、实质肿瘤科的Brian Rini医师表示，该研究结果是有效的，特别是因为目前没有建立RCC病患使用sunitinib和 sorafenib治疗之后恶化的标准照护，重点是，这不全然是第二线研究，对一些病患来说，可能是第三或第四线。
　　
　　检视这些研究资料，Rini医师指出，肾脏癌的一个重要议题是更加了解阻抗的机转；他表示，这可以帮助决定后续治疗的选择，不论是针对不同的路径、或者是同一路径但不同方法、或者以更强效的方式针对路径；有一些正在进行的第三期研究或许可以为此带来一线希望。
　　
　　美国临床肿瘤医学会(ASCO)第44届年会：摘要LBA5026。发表于2008年5月31日。摘要。

Everolimus Prolongs Progression-Free Survival in Metastatic Renal CancerBy Roxanne Nelson
Medscape Medical News

June 1, 2008 (Chicago, Illinois) — Patients with metastatic renal cell carcinoma (RCC) who received everolimus (RAD001) had significantly better progression-free survival than those who received standard care, report researchers here at the American Society of Clinical Oncology 44th Annual Meeting. At 6 months, in patients treated with everolimus, RCC had not progressed in 26%; in those treated with placebo, RCC had not progressed in 2%. The median progression-free survival was 4 months in the everolimus group and 1.9 months in the placebo group."Over the past few years, there has been a dramatic change in the way we treat renal cell carcinoma, because of our growing knowledge of its biology and the development of targeted therapy," said lead author Robert J. Motzer, MD, attending physician at Memorial Sloan-Kettering Cancer Center, in New York, New York. "Treatment with sunitinib or sorafenib has become the standard of care."However, effective treatments are needed for patients who experience disease progression on sunitinib and sorafenib. "This is a setting of unmet need," said Dr. Motzer. "At some point all patients develop resistance to these agents."Everolimus is a derivative of the natural macrocyclic lactone sirolimus and has both immunosuppressant and antiangiogenic properties. It targets the cellular protein mTOR, a regulator of signaling pathways associated with the abnormal growth, proliferation, and survival of cancer cells. In addition to RCC, it is currently being evaluated in the treatment of several cancers, including lymphoma and neuroendocrinal tumors.Everolimus showed antitumor activity in a single-group phase?2 trial of pretreated patients with metastatic RCC. The current study was a phase?3 study of 410 patients with metastatic RCC who had progressed on previous treatment. "The study was conducted worldwide and it was a heavily pretreated group," Dr. Motzer. "Many patients had received 2 or 3 prior therapies."The patients were randomized to receive either everolimus (272 patients) or the best supportive care (138 patients). All of the patients had previously been treated with other agents: 71% with sunitinib, 55% with sorafenib, and 26% with sunitinib and sorafenib. The primary end point was progression-free survival, determined by independent review."It was not overall survival because of concerns for our patients," said Dr. Motzer. "We wanted the time for a crossover."A final analysis had been planned, but the second interim analysis showed that there was a large benefit for the patients taking everolimus. The everolimus group had a 70% decrease in cancer progression, with a strong hazard ratio of 0.30. When this was determined, the independent monitoring committee recommended that the study be discontinued. The study was unblended at the time it was stopped, and 81% of the patients taking placebo who had experienced disease progression crossed over to everolimus.The drug was relatively well tolerated. Adverse events in 10% of patients who received everolimus were severe enough to warrant discontinuation, compared with 4% in the placebo group. A reduction in dose, secondary to adverse events, was required by 4% of the everolimus group and less than 1% of the placebo group.