ALK抑制剂alectinib（CH5424802）相关信息

CH5424802被FDA授予突破性药物
Roche Gets Breakthrough Status for Lung Cancer Drug

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation for Roche’s alectinib based on data that will be presented at European Cancer Congress (ECC), according to the company.

Despite significant recent advances, patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) still frequently develop resistance to available treatment and their disease relapses. A number of patients develop new tumours in the brain because many anti-cancer therapies have difficulty crossing the blood-brain barrier. At ECC, encouraging efficacy and safety data in patients with metastatic NSCLC that has progressed on crizotinib will be presented for alectinib, a promising investigational 2nd generation ALK inhibitor, in a late breaking report.

Alectinib was created by Chugai Pharmaceutical Co. Ltd., a member of the Roche group.

In addition, Roche announced that new data for several of its established and other investigational cancer medicines will be presented at the ECC in Amsterdam between September 27 to October 1, 2013. Roche medicines will be featured in more than 138 scientific presentations. The data presented come from 18 Roche medicines that are directed against a broad range of therapeutic targets.

"At ECC this year we will present important updates for both investigational and approved medicines," said Hal Barron MD, chief medical officer and head of Global Product Development at Roche. "These data reflect our commitment to develop new targeted anti-cancer medicines as well as to explore how our approved medicines, such as Zelboraf, Avastin and Herceptin, can benefit more patients."

罗氏肺癌药获得FDA突破性治疗药物资格
译者：elite_xy
来源：http://www.dddmag.com/news/2013/ ... us-lung-cancer-drug

据罗氏公司的消息透露，美国食品药品监督管理局(FDA)基于罗氏公司将在欧洲癌症大会(ECC)公布的关于alectinib的数据，授予其肺癌治疗药物alectinib突破性治疗药物资格。

虽然近阶段肺癌的治疗手段有重大进展，但是换有渐变性淋巴瘤激酶(ALK)阳性的非小细胞肺癌(NSCLC)的病例仍然经常会发展对现有的治疗手段出现耐药，而且他们的疾病也经常会复发。因为目前大多数抗肿瘤药都无法穿过血脑屏障(BBB)，所以许多病例的脑部会出现新发肿瘤。在欧洲癌症大会上，将会发布超过克里唑替尼的alectinib的在转移性非小细胞肺癌病例中令人鼓舞的有效性和安全性数据，在最近的重大报告中现实，alectinib是一个有前途的第二代渐变性淋巴瘤激酶抑制剂。

Alectinib由日本中外制药株式会社开发，该公司为罗氏集团的一个下属分公司。

此外，罗氏公司还宣布，将在2013年9月27日至2013年10月1日阿姆斯特丹举办的欧洲癌症大会上，发布其几个其已经确定的和一些正在研发状态的抗肿瘤药的最新数据。罗氏制药公司将展出超过138篇科学演讲稿。这些数据来自18个针对不同领域治疗靶标的罗氏公司的药物。

“在今年的欧洲癌症大会上，我们将展示一些在研的和已经批准的药物的最新数据，”罗氏全球产品开发主管，首席医疗官HalBarron医学博士说：“这些数据反映了我们致力于开发新的靶向抗癌药物，已经我们的一些已经被批准上市的药物，如威罗菲尼，阿瓦斯丁和赫赛汀是如何最患者带来益处的。”

补充些基本信息
CH5424802是有效的ALK抑制剂，IC50为1.9 nM,对L1196M突变型敏感，作用于ALK比 PF-02341066(克药）, NVP-TAE684 和PHA-E429选择性高。

见http://www.selleck.cn/products/ch5424802.html

Alectinib？这是不是说，又有一种新的药物即将出现了，就像 是易瑞沙或特罗凯一样的杰出

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

请问如果克药耐药后能否再用此药呢？

直接上802会比克更好？

[ESMO2013]新药对ALK阳性NSCLC脑转移有效

新的ALK抑制剂-alectinib用于治疗ALK基因重排的非小细胞肺癌患者，其对Crizotinib耐药的患者仍然有效。它能显著减少脑转移，此前尚未发现其他药物有此疗效。

在2013年欧洲癌症大会上，来自美国加州大学健康科学临床的Sai-Hong Ignatius Ou教授报告了alectinib的最新研究数据。

他强调：对疾病进展的NSCLC患者而言，alectinib减少肿瘤脑转移是首次发现。这些患者通常会接受放疗或者手术，而脑转移常常是致命的。之前我们无计可施，但是现在这些研究发现患者可能有新的生机。

Crizotinib敏感和Crizotinib耐药人群

Crizotinib是全球迄今为止唯一治疗ALK阳性的晚期NSCLC的ALK抑制剂。其在美国被批准用于任意阶段治疗，而在欧洲被批准用于二线治疗。在一项3期试验中发现对ALK基因重排的晚期NSCLC患者，Crizotinib疗效优于标准化疗。详细资讯：Xalkori对ALK+晚期NSCLC疗效显著

但是接受Crizotinib治疗的患者多数在平均8个月内疾病进展，因而需要更有效的ALK抑制剂，Ou教授如是说。他解释到其报告的1期alectinib试验结果是治疗的开端，可将晚期和耐药的NSCLC治疗向前推进。

研究具体内容：

研究中从美国6个地区招募了47例对Crizotinib耐药的患者。所有入组的志愿者均有一项ALK的重排且Crizotinib治疗失败，但是未曾接受其他ALK抑制剂治疗。所有患者均存在无症状的脑转移，包括软脑膜癌，但无激素治疗情况下，临床症状稳定超过2周。

在这项剂量渐增的研究中，患者接受一天两次的alectinib，计量分别是300 mg, 460 mg, 600 mg, 760 mg或者900mg直至疾病进展或无临床受益。主要研究目的是为2期试验摸索剂量。最终决定使用一天两次600mg的剂量。

至今通过肿瘤萎缩、无新的病灶或已有肿瘤无生长来评估的总体反应率相对不错—在所有队列中达到了54.5%，Ou教授说道，alectinib每天两次600mg或更大剂量时，ORR是59.5%。该研究仍在进行，中位持续时间尚未达到。“但是目前已经超过了4个月。”Ou教授声称。

在美国启动的试验中，参与Alectinib治疗的对Crizotinib耐药的ALK-阳性NSCLC患者在被纳入2期试验之前，在Crizotinib治疗失败后必需接受活组织检查；在alectinib治疗后病情再度进展时也必需接受活组织检查。

全球2期试验(Accalia G2L)正在积极招募患者。Ou教授表示罗氏公司正计划3期头对头地比较alectinib和crizotinib试验，次要终点是脑转移复发时间。最早在2014年启动。

减少脑转移

Ou教授指出，这项研究的另一个重要发现是alectinib显著减少脑转移。在NSCLC患者脑转移对照组中真正未达到需求。作为晚期“肿瘤逃逸”现象，患者脑部出现肿瘤进展。一般发生在7-8个月期间，这是由于全身控制良好的患者体内分子亚群中Crizotinib选择压力所致。

在基线时，47例患者中有21例有中枢神经系统转移，对这一规模的研究而言是异乎寻常得高。“我们研究开始时就有诸多脑转移的患者，但是只有4例患者由于疾病进展脱离研究，其余患者均有效”Ou教授报道。在alectinib治疗前和治疗后，使用MRI扫描检查脑转移的患者。3周后在治疗前62.5px的病灶萎缩了47%。

两例肿瘤细胞浸润至脑膜内的软脑膜癌患者治疗反应良好，其中一例患者接受姑息治疗使用，脊髓液转移灶清除提示他达到了疾病完全缓解。这个不吸烟的29岁患者同病魔斗争了7年，由于发生了软脑膜癌，她出现面部麻木和中风样表现，但是接受alectinib治疗6周内，她症状消失，病情好转。

根据Ou教授所说，alectinib不同于其它治疗NSCLC药物，是因为它有很好脑组织渗透性，能穿越血脑屏障，在脑组织内达到更高的浓度。不幸的是，Crizotinib治疗时，肿瘤有很强的选择压力，Crizotinib在体内多器官实现了对肿瘤的很好克制，但这些克制事实上促进脑肿瘤发生。

在下月召开的世界肺癌大会时会公布alectinib治疗ALK阳性NSCLC患者脑转移的临床疗效的更多信息。

专家观点：

尽管1期试验研究的病例数少，这一新的ALK抑制剂的疗效令人感兴趣。

来自意大利BolognaAzienda USL Bellaria-Maggiore医学肿瘤科的Alba A.Brandes教授表示。“靶向药物在治疗脑转移中的角色仍充满挑战”，她说“但是其他药物的信息和肿瘤的类型似乎指向同一方向，这提示特定肿瘤类型生物敏感性—如ALK突变或EGFR突变的NSCLC， HER2阳性的乳腺癌和BRAF突变的黑色素瘤—比转移的部位更为重要。”

“此外，在未来的临床实验中，即便crizotinib治疗失败，由于抗ALK药物的特定活性，脑转移的患者不应被排除在外。“她说。

来自澳大利亚维也纳大学，同时也作为EORTC脑肿瘤组联合主席的Matthias Preusser教授对此研究表示欢迎。他解释道：半数NSCLC患者会发生脑转移，局部治疗如放疗、立体定向放射外科和神经外科切除是治疗晚期病例的经典方案。他说：“系统治疗的数据有限，由于血脑屏障的存在，许多药物不能在脑组织内达到足够的药效浓度。”

“应该祝贺作者们招募脑转移的NSCLC患者参与早期试验，在之前的多数临床实验中，这类患者不幸地拒之门外。“Dr. Preusser补充道。

Chugai公司向日本提交了盐酸alectinib治疗ALK融合基因阳性非小细胞肺癌的新药申请
New Drug Application Filed for ALK Inhibitor “Alectinib Hydrochloride”for the Treatment of ALK Fusion Gene Positive Unresectable, Recurrent / Advanced Non-Small Cell Lung Cancer
October 8, 2013 (Tokyo) - Chugai Pharmaceutical Co., Ltd. announced today that it has filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW)on October 7, 2013, for ALK (Anaplastic Lymphoma Kinase) inhibitor “alectinib hydrochloride (Development code: AF802, Roche Development Code: RG7853, Compound number: CH5424802)” for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC). On September 13, 2013, alectinib hydrochloride for the treatment of “ALK fusion gene positive unresectable, recurrent / advanced non-small cell lung cancer” was designated as orphan drug by MHLW.
Chugai filed the application with the MHLW based on the results from a Japanese phase I/II clinical trial, before the phase III clinical trial results will be available. The clinical trial was conducted at 13 medical institutions in Japan in ALK fusion gene positive lung cancer patients with a treatment history of chemotherapy. The clinical trial was conducted in two phases; the phase 1 portion was conducted to evaluate safety and to determine the recommended dose (24 patients), and the phase 2 portion was conducted to evaluate the efficacy and safety of the confirmed recommended dose (46 patients).
As a result, the recommended dose was determined to be 300 mg twice daily in phase 1. Phase 2 was conducted using the recommended dose, and as a result, tumor regression was observed in 43 (93.5%) out of 46 patients. Regarding safety, there were no treatment-related deaths and grade 4 or higher serious adverse reactions assessed according to CTCAE (Common Terminology Criteria for Adverse Events) defined by the Japan Clinical Oncology Group. The most frequently observed grade 3 or higher adverse reactions were neutropenia and increase in creatine phosphokinase (CPK). The incidence of both adverse events was 2 (4.3%) out of 46 patients*.
Based on the results of an American Phase I dose-escalation study of patients with ALK fusion gene positive NSCLC whose disease had progressed on crizotinib therapy, in addition to Japanese Phase I/II clinical trial results, alectinib hydrochloride was found to meet the criteria for Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) on June 26, 2013. The results of the American study were presented as a late-breaker at the 2013 European Cancer Congress (ECC) in Amsterdam.
As the top pharmaceutical company in the field of oncology in Japan, Chugai will work for the approval to provide patients and medical professionals with new treatment options as soon as possible.

http://www.chugai-pharm.co.jp/hc ... 20131008113000.html
New Drug Application Filed for ALK Inhibitor “Alectinib Hydrochloride”
for the Treatment of ALK Fusion Gene Positive
Unresectable, Recurrent / Advanced Non-Small Cell Lung Cancer

October 8, 2013 (Tokyo) - Chugai Pharmaceutical Co., Ltd. [Main Office: Chuo-ku, Tokyo. Chairman & CEO: Osamu Nagayama (hereafter, “Chugai”)] announced today that it has filed a new drug application to the Ministry of Health, Labour and Welfare (MHLW) on October 7, 2013, for ALK (Anaplastic Lymphoma Kinase) inhibitor “alectinib hydrochloride (Development code: AF802, Roche Development Code: RG7853, Compound number: CH5424802)” for the treatment of ALK fusion gene positive non-small cell lung cancer (NSCLC). On September 13, 2013, alectinib hydrochloride for the treatment of “ALK fusion gene positive unresectable, recurrent / advanced non-small cell lung cancer” was designated as orphan drug by MHLW.

Chugai filed the application with the MHLW based on the results from a Japanese phase I/II clinical trial, before the phase III clinical trial results will be available. The clinical trial was conducted at 13 medical institutions in Japan in ALK fusion gene positive lung cancer patients with a treatment history of chemotherapy. The clinical trial was conducted in two phases; the phase 1 portion was conducted to evaluate safety and to determine the recommended dose (24 patients), and the phase 2 portion was conducted to evaluate the efficacy and safety of the confirmed recommended dose (46 patients).

As a result, the recommended dose was determined to be 300 mg twice daily in phase 1. Phase 2 was conducted using the recommended dose, and as a result, tumor regression was observed in 43 (93.5%) out of 46 patients. Regarding safety, there were no treatment-related deaths and grade 4 or higher serious adverse reactions assessed according to CTCAE (Common Terminology Criteria for Adverse Events) defined by the Japan Clinical Oncology Group. The most frequently observed grade 3 or higher adverse reactions were neutropenia and increase in creatine phosphokinase (CPK). The incidence of both adverse events was 2 (4.3%) out of 46 patients*.

Based on the results of an American Phase I dose-escalation study of patients with ALK fusion gene positive NSCLC whose disease had progressed on crizotinib therapy, in addition to Japanese Phase I/II clinical trial results, alectinib hydrochloride was found to meet the criteria for Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) on June 26, 2013. The results of the American study were presented as a late-breaker at the 2013 European Cancer Congress (ECC) in Amsterdam.

As the top pharmaceutical company in the field of oncology in Japan, Chugai will work for the approval to provide patients and medical professionals with new treatment options as soon as possible.

* Seto et al., Lancet Oncol. 14: 590-598 (2013)


About alectinib hydrochloride (AF802, CH5424802)
Alectinib hydrochloride is an oral ALK inhibitor created by Chugai Kamakura Research Laboratories. Alectinib hydrochloride is a drug candidate that matches with the PHC strategy that selects an appropriate drug for patients expected to obtain the therapeutic effect by using biomarkers and/or diagnostic tools. It has been reported that ALK fusion genes are expressed in two to five percent of the patients with NSCLC1). It is considered that the ALK kinase activity is constantly increased in the cells with this fusion gene, and transforms the cells into tumor cells2, 3). Alectinib hydrochloride demonstrates its anti-tumor effect by selectively inhibiting the kinase activity, and inhibiting the proliferation of tumor cells and inducing apoptosis4). The rights to alectinib hydrochloride in overseas countries including Europe and the US have been licensed to F. Hoffmann-La Roche Ltd. [Head Office: Basel, Switzerland. CEO: Severin Schwan], and the clinical trials of alectinib hydrochloride (Roche Development Code: RG7853) are currently ongoing in the US, Europe and other countries.
1)         Biomarker committee of The Japan Lung Cancer Society, Guidelines for ALK gene tests in lung cancer patients
2)         Soda et al., Nature. 448: 561-566 (2007)
3)         Takeuchi et al., Clin Cancer Res. 15: 3143-3149 (2009)
4)         Sakamoto et al., Cancer Cell. 19: 679-690 (2011)

About Breakthrough Therapy Designation
Breakthrough Therapy designation is enacted as part of the FDA Safety and Innovation Act (FDASIA) signed into law in July, 2012. This programme is aimed to expedite the development and review of drugs for serious or life-threatening conditions. To be granted Breakthrough Therapy Designation, preliminary clinical evidence demonstrating that the drug may have substantial improvement on at least one clinically significant endpoint over available therapy is required. Although the Breakthrough Therapy Designation is distinct from the FDA’s other programmes to expedite drug development and review, all the benefits of fast track designation are available to those who have received a Breakthrough Therapy Designation.

http://www.oncologypractice.com/ ... 1f1b6e5c1117bb.html


A total of 47 patients were enrolled in the phase I study and treated with twice-daily alectinib at doses ranging from 300 mg to 900 mg. All patients had adenocarcinoma histology, an ECOG performance status of 0-2, and no prior exposure to other ALK inhibitors.

Two dose-limiting toxicities occurred at the 900-mg dose – a grade 3 headache and grade 3 neutropenia requiring dose interruption for 7 days. No patient had to be dose reduced at 600 mg twice daily, which was identified as the recommended phase II dose.

Overall, there were very few grade 3/4 treatment-emergent adverse events, said Dr. Ou of the Chao Family Comprehensive Cancer Center at the University of California Irvine Medical Center, Orange. Most were increased gamma-glutamyl transpeptidase, neutrophil decrease, and hypophosphatemia.

The most common toxicities were fatigue (30%), myalgia and peripheral edema (17%), elevated creatine phosphokinase (15%), and photosensitivity (13%).

Among the 21 patients with brain metastases at baseline, 13 had partial responses to alectinib at varying doses, 6 had stable disease, 1 had progressive disease, and 1 had a pending evaluation.

Dr. Ou said that a new 150-mg capsule has been formulated to reduce the number of capsules needed each day and that a phase II study (Accalia G2L) of alectinib is underway in crizotinib-resistant ALK-positive non–small cell lung cancer. A phase III head-to-head comparison between alectinib and crizotinib is also planned, with the protocol to be completed by January 2014, he said.