crizotinib（克唑替尼，商品名：XALKORI® ）是6年来美国FDA批准的第一个治疗肺癌的新药

美国食品和药物管理局（FDA）2011年8月26日批准了ALK酪氨酸激酶抑制剂Crizotinib（克里唑蒂尼，商品名：XALKORI ®胶囊，辉瑞公司）的加速新药申请，用于治疗间变性淋巴瘤激酶（ALK）阳性的局部晚期或转移性非小细胞肺癌（NSCLC）。同时还批准了雅培公司生产的Vysis ALK Break-Apart FISH检测试剂盒，使用该试剂盒检测ALK阳性的非小细胞肺癌患者批准采用克里唑蒂尼治疗。

克里唑蒂尼是全球首个口服间变型淋巴瘤激酶（ALK）抑制剂。克里唑蒂尼通过抑制ALK可以阻断一系列关键的肿瘤细胞生长存活的通路。对于ALK基因重排的患者，克里唑蒂尼显示出了显着的活性，并可延长生存期。
克里唑蒂尼的有效性和安全性经2项多中心单组临床试验验证，临床研究结果显示，83%的患者的肿瘤某种程度上得到了缩小，其中有54%的患者的肿瘤缩小达1/3或1/3以上。

克里唑蒂尼不良反应轻微，最常见的不良反应为视力障碍、恶心、腹泻、呕吐、水肿和便秘。

部分中文Xalkori胶囊处方资料（仅供参考）

XALKORI® (crizotinib)胶囊，口服

美国初始批准： 2011

适应证和用途
XALKORI是一种激酶抑制剂适用于有局部晚期或转移非小细胞肺癌(NSCLC)患者的治疗是当用一种FDA批准的检验变性淋巴瘤激酶(ALK)-阳性。(1) 这个适应症是基于反应率。没有可以得到的资料显示用XALKORI报道患者的结局或生存改善。

剂量和给药方法
（1）250 mg口服每天2次有或无食物。
（2）根据个体安全性和耐受性可能需要给药中断和/或剂量减低至200 mg口服每天2次，然后如需要进一步减低至250 mg口服每天1次。

剂型和规格
（1）XALKORI胶囊: 250 mg和200 mg.

禁忌证
无

警告和注意事项
（1）肺炎：严重，包括致命性，治疗-相关肺炎曾观察到。为指示性肺炎肺部症状监视患者。有治疗-相关肺炎诊断患者中永远终止。
（2）肝实验室异常：曾发生ALT和总胆红素同时升高。每月监视和当临床指示有2-4级升高患者用更频繁检验。当指示，暂时停止，减低剂量，或永远终止XALKORI。
（3）QT间隔延长：有病史或QTc延长倾向患者，或服用已知延长QT间隔药物, 应考虑监视心电图定期和电解质。
（4）ALK检验：为选择用ALKORI治疗患者需要用一种FDA批准的检验检测ALK-阳性NSCLC，适用于这个用途。
（5） 妊娠：当给予妊娠妇女时XALKOR可能致胎儿危害。
不良反应
最常见不良反应(≥25%)是视力障碍，恶心，腹泻，呕吐，水肿，和便秘。

药物相互作用
（1）CYP3A抑制剂：避免XALKORI与强CYP3A抑制剂同时使用。
（2）CYP3A诱导剂：避免XALKORI与强CYP3A诱导剂同时使用。
（3）CYP3A底物：对共同给药药物主要被CYP3A代谢可能需要减低剂量。避免XALKORI与有狭窄治疗指数CYP3A底物同时使用。

注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
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原产地英文商品名:
XALKORI 250MG/CAP 60CAPS/BOTTLE
原产地英文药品名:
CRIZOTINIB
中文参考商品译名:
XALKORI 250毫克/胶囊 60胶囊/瓶
中文参考药品译名:
克卓替尼，克里唑蒂尼
生产厂家中文参考译名:
辉瑞
生产厂家英文名:
PFIZER
---------------------------------------------------------------
原产地英文商品名:
XALKORI 200MG/CAP 60CAPS/BOTTLE
原产地英文药品名:
CRIZOTINIB
中文参考商品译名:
XALKORI 200毫克/胶囊 60胶囊/瓶
中文参考药品译名:
克卓替尼，克里唑蒂尼
生产厂家中文参考译名:
辉瑞
生产厂家英文名:
PFIZER

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Xalkori(crizotinib)

Crizotinib Approved For Late-stage NSCLC
Under its accelerated approval program, the FDA has approved crizotinib (Xalkori, Pfizer) for patients with locally advanced or metastatic, non-small cell lung cancers (NSCLC) that express the abnormal anaplastic lymphoma kinase (ALK) gene.

The drug is being approved with a companion diagnostic test, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular), which will identify patients who have the abnormal gene.

Approximately 1% to 7% of patients with NSCLC have the ALK gene abnormality, which causes cancer development and growth. Patients with this form of lung cancer are typically nonsmokers. Crizotinib works by blocking kinases, including the protein produced by the abnormal ALK gene. Crizotinib, which is available in pill form, is taken twice a day as a single-agent treatment.

Crizotinib’s safety and effectiveness were established in two multicenter, single-arm studies enrolling 255 patients with late-stage ALK-positive NSCLC. A sample of a patient’s lung cancer tissue was collected and tested for the ALK gene abnormality prior to study enrollment. The studies were designed to measure objective response rate (ORR). Most patients in the studies had received prior chemotherapy.

In one study, the ORR was 50% with a median response duration of 42 weeks. In another, the ORR was 61% with a median response duration of 48 weeks.

The most common side effects reported in patients receiving crizotinib included vision disorders, nausea, diarrhea, vomiting, edema and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light and visual field defects. Crizotinib use also has been associated with pneumonitis, which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with crizotinib. The drug should not be used in pregnant women.

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Xalkori (Crizotinib) is a oral drug indicated for the treatment of non-small cell lung cancer. The drug is developed and manufactured by Pfizer.

Crizotinib obtained orphan drug designation from the US FDA in September 2010. It was granted fast track designation in December 2010. Pfizer filed a new drug application in May 2011.

The FDA approved the drug for the treatment of metastatic anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer in August 2011. The approval was based on trial data of 255 patients enrolled in two clinical trials namely Phase II-Profile 1005 and Phase I-Study 1001.

Pfizer submitted a marketing authorisation application to the European Medicines Agency (EMA) in August 2011. The drug is currently under review by the EMA.

The drug also obtained orphan drug designation in Japan in January 2011. New drug application was submitted to the Japanese Ministry of Health, Labour and Welfare in May 2011.

Crizotinib – mechanism of action
Crizotinib is an oral medication having the ability to inhibit ALK and c-MET.

ALK is an enzyme encoded by ALK gene. It can be carcinogenic due to mutation or due to formation of a fusion with another gene thereby leading to ALCL (anaplastic large-cell lymphomas), NSCLC or neuroblastoma.

After ALK inhibition, the cell signalling necessary for the growth of tumour and survival in various cell pathways is blocked.

Clinical trials
Study 1006, a Phase I study, is being conducted to evaluate safety, efficacy, pharmacokinetics and pharmacodynamics of Crizotinib in 70 NSCLC patients. The trial, which began in April 2010, is expected to be complete by May 2012.

Around 175 patients will be enrolled in another Phase I trial being conducted to evaluate the safety of the drug and determine the maximum tolerable dose.

A Phase II study named PROFILE 1005 was initiated in 400 NSCLC patients in January 2010. The trial is being conducted to evaluate the safety and efficacy of the drug in ALK positive NSCLC patients. The trial is expected to be complete by September 2013.

Phase I/II study 1002 was initiated in January 2010 in 175 patients having NSCLC. It will evaluate the safety and efficacy of Erlotinib alone in comparison with Erlotinib in combination with Crizotinib. The enrolled patients are being administered either 150mg of erlotinib alone or 150mg of erlotinib in combination with 200-250mg of crazotinib. The primary end point is to determine the maximum tolerable dose and the progression free survival. The trial is expected to be complete by July 2014.

The FDA approval of Xalkori was based on the trial data of 255 patients from PROFILE 1005 and Study 1002.

The objective response rate (ORR) of PROFILE 1005 was 50%. The patients were treated for an average period of 22 weeks. Around 79% of tumour responses were observed during the first eight weeks.

In Study 1001, patients were treated for an average period of 32 weeks. The ORR was 61% and around 55% of this was observed during the first eight weeks.

Phase III development
Two Phase III trials PROFILE 1007 and PROFILE 1014 are currently being conducted in patients with NSCLC.

PROFILE 1007 is being conducted to determine the progression free survival of patients treated with Crizotinib in comparison with those treated with Docetaxel or Premetrexed. The trial with and estimated enrolment of 318 patients was initiated in September 2009 and is expected to be completed by September 2012. Patients from the chemotherapy arm of Phase III 1007 trial also have an option to be administered with crizotinib in the Phase II PROFILE 1005 study.

Around 334 NSCLC patients have been enrolled in Phase III PROFILE 1014 trial. The trial, which began in January 2011 will determine the anti-cancer effects of the drug and will compare them to those of the chemotherapy in ALK positive patients. The study has a scheduled primary completion date of October 2013. The entire trial is expected to be complete by December 2013.

Non-small cell lung cancer
Non-small cell lung cancer (NSCLC) is the most common kind of lung cancer. The growth and progression of NSCLC is slower than that of small cell lung cancer. Adenocarcinomas, squamous cell carcinomas and large cell carcinomas are the different types of NSCLC.

NSCLC is usually caused by smoking. It also occurs in people who work near asbestos, products using chloride and formaldehyde, certain alloys, paints, pigments and preservatives.

Symptoms of NSCLC include coughing up blood, shortness of breath, wheezing, chest pain, loss of appetite, losing weight without trying and fatigue.

Around 45,000 patients worldwide are diagnosed with ALK positive NSCLC every year.