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2011年8月26日，辉瑞公司的XALKORI® (crizotinib)胶囊获得美国食品药品管理局(FDA)批准，这是第一个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药品，用于治疗通过FDA批准的检测方法诊断为ALK阳性的局部晚期或转移的非小细胞肺癌(NSCLC) 。也是近6年来美国FDA批准的第一个治疗肺癌的新药。
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。
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。
为报告怀疑不良反应联系Pfizer Inc.电话1-800-438-1985或FDA电话1-800-FDA-1088或www.fda.gov/medwatch.
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。
如何提供/存储和搬运
250毫克胶囊
硬胶囊，粉红色不透明的帽子和身体帽上印黑色墨水“辉瑞”，“250 CRZ”在身体上;提供：
60胶囊瓶：NDC0069-8140-20
200毫克胶囊
硬胶囊，粉红色不透明的帽子和白色不透明体帽上印黑色墨水“辉瑞”，“200 CRZ”对身体可在：
60胶囊瓶：NDC0069-8141-20
储存在室温20°〜25° C（68°〜77° F）;游览允许在15 °至30° C（59 °〜86° F）[见美国药典控制室温]。
Xalkori - Treatment for Non-Small Cell Lung Cancer
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.
FDA批准Xalkori和伴随诊断试验用于晚期肺癌
2011年8月26日，辉瑞和美国食品药品管理局(FDA)宣布，Xalkori(crizotinib)已获准用于治疗特定的晚期(局部进展性或转移性)、表达间变性淋巴瘤激酶(ALK)基因的非小细胞肺癌(NSCLC)患者。罹患这种肺癌的患者通常不吸烟。Xalkori被批准与雅培的一种伴随诊断基因检测——Vysis ALK Break Apart FISH Probe Kit——共同使用。该检测用于确定患者的癌症是否表达异常的ALK基因。
Xalkori是一种激酶抑制剂，其治疗肺癌的适应证是以应答率为基础的。尚无数据证实该药可改善患者报告的预后或生存率。Xalkori被认为通过阻断多种细胞通路的信号传导而发挥疗效，据称这些细胞通路对于肿瘤细胞的生长和生存至关重要，该药可使肿瘤趋于稳定和退化。ALK基因的改变被认为是NSCLC之类肿瘤进展的关键驱动因素。
Xalkori的安全性和有效性已在2项多中心、单组研究中获得证实，这2项研究共纳入了255例晚期ALK阳性NSCLC患者。研究者在招募患者前采集其肺癌组织样本，进行ALK基因检测。多数入组患者曾接受过化疗。在其中一项研究中，客观应答率为50%、中位应答时间为42周，而在另一项研究中分别为61%和48周。
两项研究中最常报告的不良反应均为视力障碍、恶心、腹泻、呕吐、浮肿和便秘。两项研究中均有至少4%的患者发生3或4级不良反应，包括谷丙转氨酶水平升高和中性粒细胞减少。
使用Xalkori还与肺炎相关，甚至可危及生命。发生治疗相关性肺炎的患者必须永久停用Xalkori。
Xalkori为胶囊制剂，每日服药2次，单药治疗。
辉瑞研究新的发现；克里唑蒂尼（Xalkori；crizotinib）治疗儿童癌症有良好药效
新药Xalkori此前被批准用于ALK基因突变造成的非小细胞肺癌的治疗。日前Xalkori被用于患有罕见癌症的儿童进行治疗实验,这些患病癌症ALK基因突变,并最终取得了成功。这也证明针对特定基因的靶向癌症药物对于癌症可能具有广泛的适应性。
Xalkori被用于治疗70名患有不同癌症的儿童患者,这些患者都或多或少的受益。对于间变性大淋巴瘤,Xalkori取得了惊人的成果。在8名患有这种疾病的儿童中,使用Xalkori治疗后,有7名几乎完全康复,在治疗后进行的扫描中看不到任何病灶。
这一临床结果得到了专家的一致称赞,但也同时指出副作用仍可能存在。儿科肿瘤专家Link称药效“快的令人惊讶”。这项研究的主要负责人Yael Mosse也表示,“对于那些因为此前被认为毫无希望的孩子来说,Xalkori会是新的希望。” | 
