8月26日，美国食品和药物管理局（FDA）批准Xalkori (crizotinib)治疗某些有局部晚期或转移性非小细胞肺癌(NSCLC)的病人，其肿瘤表达异常间变型淋巴瘤激酶（ALK）基因。

Xalkori和配套的诊断性试验一同获准，有助于确定病人是否存在异常ALK基因，这个基因检测称为Vysis ALK分离FISH探针检测盒。Xalkori是FDA今年批准的此类靶向治疗的第二个。

ALK基因异常导致癌症发生与生长。NSCLC病人中约有1%~7%的病人有ALK基因异常。这种类型的肺癌病人通常是非吸烟者。Xalkori通过阻断激酶而发挥作用，包括由异常ALK基因产生的蛋白。Xalkori是单药治疗，1片，每日2次。

Xalkori的安全性和有效性是经2项多中心、单组研究确定的，研究共纳入255例晚期ALK阳性的NSCLC病人。在纳入研究前，病人的肺癌组织标本被采集，并作ALK基因异常的检测。该研究的设计是观测客观疗效反应率，以及肿瘤完全或部分萎缩病人的百分比。纳入研究的病人大多既往接受过化疗。

在一项研究中，客观有效率为50%，中位疗效维持时间为42周。在另一项研究中，客观有效率为61%，中位疗效维持时间为48周。

FDA批准Vysis ALK分离FISH 探针检测盒是基于上述研究之一的数据。Xalkori的审查被列入FDA优先审查项目。

“肿瘤学研究的趋势仍是靶向治疗”，美国FDA体外诊断设备评价和安全办公室主任Alberto Gutierrez说。“这种检测是一个例子，说明了配套诊断的重要作用，它可以使有严重和致命疾病的患者及时得到最安全和最有效的治疗。”

接受Xalkori治疗病人最常报告的副作用包括视力障碍、恶心、腹泻、呕吐、水肿和便秘。视力障碍包括视力损害、闪光、视力模糊、悬浮物、复视、对光敏感和视野缺损。用Xalkori还与肺部炎症相关，可能会危及生命。患有治疗相关肺炎的患者应永久停止Xalkori治疗。本药不应用于妊娠妇女。

INDICATION
XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.
Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated.

Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis.

QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs.

ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.

Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4).

Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia.

Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder.
Neuropathy attributed to study drug was reported in 34 (13%) patients. Grade 2 motor neuropathy and grade 3 peripheral neuropathy were reported in 1 patient each.
Bradycardia was reported in 12 (5%) patients treated with XALKORI. All of these cases were grade 1 or 2 in severity.
Complex renal cysts were reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases.
Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were observed in 5.2%, 0.4%, and 11.4% of patients, respectively.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Use caution in patients with severe renal impairment or patients with end-stage renal disease.

最后更新：
2011年9月12日

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]。

 
Pharmacological Class:
Tyrosine kinase inhibitor.

Active Ingredient(s):
Crizotinib 200mg, 250mg; caps.

Indication(s):
Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

Pharmacology:
Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib is an inhibitor of receptor tyrosine kinases that include ALK, Hepatocyte Growth Factor Receptor (HGFR, c-MET), and Recepteur d’Origine Nantais (RON).

Clinical Trials:
Crizotinib was investigated in two multi-center, single-arm studies (Studies A and B). In Study A, ALK-positive NSCLC was identified using the Vysis ALK Break-Apart FISH Probe Kit. In Study B, ALK-positive NSCLC was identified using a number of local clinical trial assays. The primary efficacy endpoint in both studies was Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors. Duration of Response was also evaluated. At study completion, 136 patients in Study A and 119 patients in Study B were analyzed. The median duration of treatment was 22 weeks in Study A and 32 weeks in Study B. Based on investigator assessments in Study A, there was 1 complete and 67 partial responses for an ORR of 50% (95% CI: 42%, 59%) and in Study B, there were 2 complete and 69 partial responses for an ORR of 61% (95% CI: 52%, 70%). Seventy-nine percent (Study A) and 55% (Study B) of objective tumor responses were achieved during the first 8 weeks of treatment. The median response duration was 41.9 weeks (Study A) and 48.1 weeks (Study B).

Legal Classification:
Rx

Adults:
Swallow whole. 250mg twice daily. Dose interruption and/or dose reduction to 200mg twice daily may be required based on individual safety/tolerability, then to 250mg once daily if necessary. Dose reduction for hematologic and non-hematologic toxicities: see literature.

Children:
Not established.

 Warnings/Precautions:
Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Monitor CBCs with differential, ALT, total bilirubin monthly, and more frequently in Grade 2–4 elevations, or if fever/infection occurs; temporarily suspend, reduce dose, or permanently discontinue as indicated. Congenital long QT syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, concomitant drugs that prolong QT interval): consider monitoring ECG, electrolytes periodically; permanently discontinue if Grade 4 QTc prolongation occurs. Test for ALK-positive NSCLC with FDA-approved test before treating. Hepatic impairment. Severe renal impairment or ESRD. Pregnancy (Cat. D); avoid. Use adequate contraception during therapy and at least 90 days after. Nursing mothers: not recommended.

Interaction(s):
Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone), grapefruit juice or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl) with narrow therapeutic indices. Caution with moderate CYP3A inhibitors. Dose reduction may be needed with coadministered drugs metabolized by CYP3A.

Adverse Reaction(s):
Vision disorder, GI upset, edema, constipation, Grade 3–4 events: ALT increased, neutropenia; elevated total bilirubin, pneumonitis (may be fatal), QT prolongation.

How Supplied:
Caps—60

Last Updated:
9/12/2011

辉瑞Xalkori口服胶囊新药对儿童癌症治愈的希望

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。”
 
一个能够治愈孩童癌症的药物重于一切。关于癌症的基因原理的发展很可能会加速抗癌药物的产生。辉瑞公司的Rob Sweetman表示，此前并不了解癌症之间的分子联系，而在现在清楚之后，将会在成年人和儿童中继续进行药物实验。
 
辉瑞公司表示，下一步进行的临床实验主要针对儿童淋巴瘤，对于儿童神经母细胞瘤的药物试验也在计划当中。虽然Xalkori很可能对于各种癌症都有效果，但目前采用的实验对象仍然是ALK基因突变的患者。