ALK抑制剂alectinib（CH5424802）相关信息

Investigational ALK Inhibitor Shows Promise in Patients With Crizotinib-Refractory, ALK-Positive NSCLC
By The ASCO Post November 15, 2013, Volume 4, Issue 18
Patients with non–small cell lung cancer (NSCLC) whose tumors have the ALK gene rearrangement usually respond to the drug crizotinib (Xalkori), with a median duration of response of approximately 10 months. In a study reported by Shirish Gadgeel, MD, of Karmanos Cancer Institute in Detroit, and colleagues at the International Association for the Study of Lung Cancer’s 15th World Conference on Lung Cancer, alectinib showed promising tumor activity in patients with ALK-positive NSCLC who were refractory to crizotinib. Alectinib is a potent ALK inhibitor recently granted Breakthrough Therapy designation by the FDA.1
Phase I Study
In a phase I dose-escalation study, alectinib was administered to 37 patients with ALK-positive NSCLC that had progressed on crizotinib and chemotherapy. The primary endpoint was dose-limiting toxicity, with secondary endpoints of efficacy, safety, and pharmacokinetic analyses. The ALK inhibitor was administered orally at doses ranging from 300 to 900 mg twice-daily until lack of clinical benefits.
Researchers found promising tumor activity with alectinib. In the 37 patients who received a therapeutic dose (≥ 460 mg twice daily), alectinib demonstrated an overall response rate of 59.5%. Median progression-free survival had not been reached after over 5 months of follow-up. No dose-limiting toxicities were observed up to the highest dose tested (900 mg twice-daily), and only one patient required dose modification due to grade 2 fatigue.
Effect on Brain Metastases
In addition, alectinib showed significant shrinkage of brain metastases,2 with only 4 of the 21 patients who were enrolled with preexisting brain metastases having discontinued treatment due to disease progression. Activity against brain metastases was observed as early as the third week of treatment, and the investigators noted that alectinib could “potentially replace or delay the need of brain radiation in ALK-positive NSCLC patients.” ■
Disclosure: Dr. Gadgeel reported no potential conflicts of interest.
References
1. Gadgeel S, Ou SH, Chiappori A, et al: A phase I dose escalation study of a new ALK inhibitor, CH542480202, in ALK+ non-small cell lung cancer patients who have failed crizotinib. Abstract O16.06. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.
2. Ou SH, Gadgeel S, Chiappori AA, et al: Consistent therapeutic efficacy of CH5424802/RO5424802 in brain metastases among crizotinib-refractory ALK-positive non-small cell lung cancer patients in an ongoing phase I/II study. Abstract O16.07. Presented at the 15th World Conference on Lung Cancer, Sydney, Australia, October 29, 2013.

http://www.inspire.com/groups/lu ... s-after-crizotinib/
Klarem: My husband started on the Chugai drug trial (CH5424802) when it was still in the dose escalation stage (Nov. 2012) and they didn't know yet what the best dose was. Fortunately for him he was put on the 600 mg dose which they now have settled on as the best. He has been on this drug for the last year and loves it. It has even less side effects than Crizotinib. The only one that he has to careful with was sun exposure. When summer 2013 arrived, even a 15 minute exposure in direct sun resulted in a severe burn.

He was progression free for exactly one year from starting the drug. He has one tumor in his lung (none elsewhere in the body) that is progressing. His doctor's treatment plan now is to cyberknife the tumor and continue on the drug and pray he gets more progression-free time. Otherwise we'll be looking for another drug to treat him. Most likely it will be LDK.

最常见的不良反应为疲劳（30％），肌肉痛和外周水肿（17％），肌酸磷酸激酶升高（15％），和光敏（13％）。
600mg*2组没有出现需要减量的病人。在900mg*2组出现的剂量相关毒性：3级头痛和3级中性粒细胞减少（4%），3级低磷血症（4%），3级谷氨酰转肽酶升高（4%）。

一个介绍ALK抑制剂的网站，需要代理访问
http://alkinhibitors.com

期待下文！

【专家访谈】ALK阳性非小细胞肺癌治疗新策略

医脉通 2014-10-24 发表评论 分享
针对EGFR或ALK突变的非小细胞肺癌的治疗手段在不断发展，临床试验已经开始研究新一代的药物和联合方案。

最近发表于The Lancet Oncology上的两个试验研究了新的药物和方案。第一个研究探索了埃罗替尼(Tarceva)联用或不联用贝伐单抗(Avastin)用于EGFR突变的晚期非鳞非小细胞肺癌患者的一线治疗的疗效。第二个研究专注于新一代ALK抑制剂alectinib,该药在克唑替尼耐药的ALK重组非小细胞肺癌患者中显示出较高的活性。

2013年，由于其在治疗ALK阳性非小细胞肺癌患者中的突出疗效，alectinib获得FDA授予的突破性治疗药物资格。此外，2014年7月，alectinib在日本被批准用于ALK阳性的非小细胞肺癌患者的治疗。

相关报道：ALK阳性NSCLC靶向新药alectinib在日本获批使用

基因泰克公司（该公司生产了alectinib、埃罗替尼和贝伐单抗）临床开发副主席Philippe Bishop博士为我们详细讲解了非小细胞肺癌治疗的新进展。

Phlippe-Bishop.jpg
Philippe Bishop, MD

问：你能讨论一下埃罗替尼±贝伐单抗方案的II期试验的结果吗？

Bishop: 150位初治的EGFR突变阳性的非小细胞肺癌患者参与了该研究。他们被随机分配到贝伐单抗+埃罗替尼组（该组75位患者）或埃罗替尼单药治疗组（该组77位患者）.

该研究是一个对比研究，探索了贝伐单抗加入到埃罗替尼中治疗EGFR突变的患者，是否有额外的益处。事实上，我们发现，联合治疗的患者的无进展生存期比埃罗替尼单药治疗的患者延长了6个月。埃罗替尼组患者的中位无进展生存期为9.7个月，而贝伐单抗-埃罗替尼联合治疗组为16个月，有了实质性的提高。风险比为0.54，p＝0.0015，有非常明显的统计学意义。这代表疾病进展率下降了46%，事实上这是非常明显的。

与传统化疗药物相比，埃罗替尼和贝伐单抗的安全性更易于管理。这提供了有效个体化治疗的机会，而不必担心一些与化疗可能出现的问题。

问：社区肿瘤学家可以从这些结果中学到什么？

Bishop: 我们赞成进行风险-收益分析，对于临床医生而言，这些研究提供了新的机会，为适合应用这些药物的患者提供了新的联合方案。要注意该联合方案在美国还未被批准使用，尽管两种药物在市场上都可以买到。这一试验是我们研发计划的重要组成部分，允许我们评估在患者中广泛开展的可能性。

问：联合方案的下一步应该是什么？

Bishop: 现在我们在寻找如何通过与认证机构对话将这些结果告知他们，使联合方案能够通过审批。目前我们正在与卫生局评估该方案，同时我们也在与美国的合作小组一起进行随机临床试验，该试验很重要，将探索这一联合方案可以为EGFR突变的患者做些什么。

以前，我们在未经选择的患者中评估了贝伐单抗+埃罗替尼联合治疗方案的疗效。但这是在我们了解到EGFR突变对药物（比如埃罗替尼）的重要性以前的事情。这些试验显示出一些疗效，但是我们看到的效果最多就是临界性的。作为计划的一部分，这些试验之后进一步的发展需要对患者进行选择。这就是设计该试验的原因。

问：你能探讨一下alectinib试验的下一步吗？如果被批准使用，它会对患者产生什么影响？

Bishop：Alectinib不仅获得了突破性药物资格，今年7月还在日本被批准使用。这一批准使用是向前发展的重要一步。该治疗能够透过中枢神经系统，我认为这是该药的重要特点。脑是非小细胞肺癌第二个容易转移的部位，在此情况下，alectinib可以穿透脑组织，比目前的ALK抑制剂更加优越。

考虑到这一点，我们目前正在进行一个临床发展计划，该计划有希望为管理世界范围内的相互交流、药物的审批、药物的获得铺平道路。我们目前正在进行两个针对克唑替尼治疗后进展的肿瘤患者的II期临床试验。希望今年的晚些时候能够得出结果。这个月末中枢神经系统转移的患者缓率的更新结果就会出来，并且会在芝加哥的多学科会议上公布。还有一个与克唑替尼作对照的头对头的III期试验(叫做ALEX试验)目前正在招募患者。

问：你能探讨一下alectinib在克唑替尼耐药的ALK重排的非小细胞肺癌患者中的安全性和有效性吗？

Bishop：要注意对于ALK突变或ALK阳性的非小细胞肺癌患者而言，这是一种诊断驱动治疗。我们的I/II期剂量研究发现：alectinib能够使ALK阳性、对克唑替尼耐药的患者的肿瘤缩小55%。通常患者对药物表现出耐药都有特殊的作用机制，能够克服这一机制是不寻常的。我们的ALK抑制剂alectinib是进一步分化的，它可以抑制克唑替尼治疗后出现的某种突变。alectinib抑制多种激酶， 其中包括接触克唑替尼后活化的激酶。

值得一提的是，该研究还纳入了52%的脑转移的患者，脑也是ALK阳性非小细胞肺癌患者复发的常见位置。了解到52%的患者是脑转移的患者，那么我们看到55%的缓解率事实上是非常令人鼓舞的。

正需要，期待～克药5个月，脑膜转～

学习了，感谢楼主！