阿斯利康目前正在进行一项AZD9291的2期研究

AZD9291是阿斯利康为使投资者相信其研发线的势力而列出的新药之一，其研发线包括几款癌症药物，以及用于糖尿病、哮喘、类风湿关节炎及银屑病的药物。总之，该英国公司预测这些新产品将有助于其销售额在2023年增长75%，达到450亿美元。
AZD9291的1期试验结果先于ASCO年会进行了发布，该试验由199名以现有EGFR药物治疗后疾病恶化的EGFR突变晚期非小细胞肺癌肺患者参与。试验中最常见副作用有腹泻和皮疹，但研究人员称，这款药物的毒性与可用的EGFR抑制剂相比小得多。
阿斯利康目前正在进行一项AZD9291的2期研究，受试者为T790M突变患者，每天用药剂量为80mg，该公司表示，这项试验将能加速这款药物于明年下半年上报。
AZD9291作为一款二线药物用于非小细胞肺癌已被FDA授予突破性治疗药物资格。阿斯利康还将研究这款药物作为一款一线治疗药物用于适合的肺癌患者。投资者渴望看到阿斯利康的定于ASCO会上发布的其它癌症数据。

New EGFR inhibitor AZD9291 shows promising activity in treatment-resistant non-small cell lung cancer
http://ecancer.org/news/5670-new ... ell-lung-cancer.php

15 May 2014

Findings from a phase I study of a new mutant selective EGFR tyrosine kinase inhibitor (TKI), AZD9291, point to a promising new treatment option for patients with advanced, EGFR mutant, non-small cell lung cancer (NSCLC) that is resistant to standard EGFR inhibitors.

Roughly 50 percent of patients experienced tumour shrinkage, and the drug worked particularly well in patients with the T790M mutation (detected in 60 percent of patients), which causes the most common form of EGFR therapy resistance.

“There is currently no standard treatment for patients with lung cancer who experience disease progression after initial therapy with an EGFR kinase inhibitor,” said lead study author Pasi A. Jänne, MD, PhD, a professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.

“Although it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for these patients, without the skin side effects we typically see with existing EGFR inhibitors.”

EGFR mutations are found in 10-15 percent of Caucasian patients and about 40 percent of Asian patients with NSCLC.

Many of these patients initially respond well to approved EGFR inhibitors erlotinib and afatinib, but all ultimately become resistant to this therapy – generally within 10 to 14 months.

Many patients become resistant to EGFR inhibitors through the development of another mutation, the T790M mutation.

The only therapy that is somewhat effective in patients with the T790M mutation is a combination of two EGFR inhibitors (afatinib and cetuximab), but it is very toxic.

In the study, 199 patients with advanced NSCLC harbouring EGFR mutations, whose disease progressed after one or more standard EGFR therapies, received different doses of AZD9291.

Responses were observed at all dose levels and in all subgroups of patients, including those with brain metastasis.

Overall, 51 percent of patients experienced tumour shrinkage.

Among the 89 patients with a confirmed T790M mutation, 64 percent responded to AZD9291, vs. 23 percent of T790M-negative patients.

The responses were still ongoing in nearly all patients at data cut-off, with the longest response lasting more than eight months.

Longer follow up is needed to determine if this therapy prolongs overall survival.

Given that these data show that AZD9291 is working more effectively for patients with the T790M mutation, future studies of this drug will be limited to this subgroup of patients, according to the researchers.

Importantly, AZD9291 selectively targets EGFR in tumours and appears to cause fewer skin toxicities than approved EGFR TKIs.

While existing drugs block both the mutant EGFR in the tumour and the normal EGFR in the skin (and other organs), which often leads to debilitating skin rash or acne, AZD9291 acts mostly on the mutant EGFR in a tumour.

This research was supported by Astra Zeneca.

ASCO Perspective

“The reduced skin toxicity seen with AZD9291 heralds greater precision in targeting cancer mutations and sparing healthy tissues which retain normal germ line EGFR status," said Peter P. Yu, MD, FASCO, ASCO President-Elect.


软件翻译：

新EGFR抑制剂AZD9291显示治疗抗性的非小细胞肺癌有前途的活性
http://ecancer.org/news/5670-new ... ell-lung-cancer.php

2014年5月15日

从我研究一个新的突变体选择性表皮生长因子受体酪氨酸激酶抑制剂（ TKI ）的阶段研究结果， AZD9291 ，指向对晚期患者， EGFR突变的非小细胞肺癌（ NSCLC）的一种很有前途的新的治疗选择，可耐标准表皮生长因子受体抑制剂。

大约50 ％的患者经历了肿瘤收缩，而该药物的工作特别好患者的T790M突变（在60 ％的患者检测到的） ，这会导致EGFR的治疗抵抗的最常见形式。

“目前还没有标准的治疗肺癌患者谁与EGFR激酶抑制剂初始治疗后出现病情恶化，说：”主要作者的Pasi A. JANNE ，医学博士，博士，医学在Dana - Farber癌症研究所教授，哈佛医学院马萨诸塞州的波士顿。

“虽然它仍然是一个有点早，我们的研究表明， AZD9291可能提供这些患者的一种有效的新治疗选择，对皮肤无副作用，我们通常与现有的EGFR抑制剂看到的。 ”

EGFR突变被发现在10％-15％的白人患者和亚洲NSCLC患者的40％左右。

许多这些患者最初反应良好，批准EGFR抑制剂埃罗替尼和afatinib ，但最终都成为抵抗这种疗法 - 一般为10至14个月内。

许多患者通过另一个突变， T790M突变的开发成为抗EGFR抑制剂。

这是在患者的T790M突变稍微有效的唯一治疗是两个表皮生长因子受体抑制剂（ afatinib和西妥昔单抗）的组合，但它是非常有毒的。

在这项研究中， 199例晚期NSCLC患者EGFR突变者，其病后的一个或多个标准的表皮生长因子受体的治疗进展，接受不同剂量的AZD9291的。

反应进行在所有剂量水平，并在所有患者亚组，包括那些有脑转移观察。

总体来说，患者的51％的肿瘤缩小。

其中89例确诊T790M突变， 64 ％的受访者对AZD9291 ，与T790M突变阴性患者的23％。

该反应仍在进行中几乎所有的患者在数据截止，最长响应持续八个多月。

再跟进的是，需要确定这种治疗延长总生存期。

鉴于这些数据表明， AZD9291工作更有效地对患者的T790M突变，这种药物的将来的研究将被限制在这个亚组的患者中，根据研究人员。

重要的是， AZD9291选择性靶向EGFR在肿瘤出现导致更少的皮肤毒性比批准的EGFR TKI的。

而现有药物阻断两者的EGFR突变在肿瘤和皮肤中的正常表皮生长因子受体（与其它器官） ，这往往会导致令人衰弱的皮疹或痤疮， AZD9291作用大多是在肿瘤的EGFR突变。

这项研究是由阿斯利康支持。

美国临床肿瘤学会透视

“减少的皮肤毒性见过AZD9291预示着更高的精度瞄准癌症突变和不遗余力的保留正常生殖系EGFR状态健康组织， ”彼得体育瑜，医学博士，外航服务公司， ASCO总统当选人说。

Potential New Drug for Some Patients With Treatment-resistant Lung Cancer
http://www.aacr.org/home/public- ... he-news.aspx?d=3182

。。。。。。
“AZD9291 is highly active in preclinical models and is well tolerated in animal models. It inhibits both activating and resistant EGFR mutations while sparing the normal form of EGFR that is present in normal skin and gut cells, thereby reducing the side effects encountered with currently available medicines,” she added.

The AstraZeneca scientists first showed that AZD9291 potently inhibited lung cancer cells with mutant EGFR, grown in lab dishes. They then tested the drug on mice bearing lung tumors with activating mutations and mice bearing lung tumors with resistance mutations. AZD9291 showed substantial tumor shrinkage in both groups of mice after 14 days of treatment. After 40 days, the researchers found no visible tumors in these mice, and this effect was sustained for more than 100 days. They also observed similar tumor shrinkage in mice that were genetically modified to develop tumors bearing both the activating and resistance mutations.

When the investigators analyzed blood samples collected from the treated mice, they identified a breakdown product of the parent compound AZD9291, which they called AZ5104, circulating in blood in addition to AZD9291. They then found that AZ5104 is also a potent inhibitor of activating and resistance EGFR mutations, and speculated that this may contribute to the efficacy seen after dosing with AZD9291.EORTC).
。。。。。。


软件翻译：

潜在的新的药物对某些患者难治性肺癌
http://www.aacr.org/home/public- ... he-news.aspx?d=3182

。 。
“ AZD9291是在临床前模型高活性和耐受性良好的动物模型。它抑制了活化和抗EGFR突变，同时保留表皮生长因子受体的正常形式，存在于正常皮肤和肠道细胞，从而降低了与现有药物中遇到的副作用， “她补充说。

阿斯利康科学家首次发现AZD9291有效抑制肺癌细胞与表皮生长因子受体突变体，在实验室菜种植。然后，他们测试了药物对小鼠肺肿瘤的活化突变和小鼠肺肿瘤的耐药突变。 AZD9291呈现大幅肿瘤缩小，两组小鼠的治疗后14天。 40天后，研究人员发现这些小鼠没有明显的肿瘤，这种作用是持续超过100天。他们也是在基因上被修改，以开发肿瘤轴承既活化和抗突变小鼠中观察到类似的肿瘤缩小。

当研究者分析了处理的小鼠采集血液样本，他们确定了母体化合物AZD9291的分解产物，他们称之为AZ5104 ，循环血液中，除了AZD9291 。然后，他们发现， AZ5104也是活化和抗EGFR突变的有效抑制剂，并推测，这可能有助于与AZD9291.EORTC给药后见到的功效） 。

希望研究人员多多出一些新药！加油！对抗！

期待新药能为更多不幸的人带来福音。