XALKORI®(Crizotinib)获得美国食品药品管理局(FDA)批准第一个也是目前唯一 一个用于治疗局部晚期或转移的 ALK阳性非小细胞肺癌的新药 ——6年来美国批准的第一个治疗肺癌的新药 XALKORI®证明了分子标志物检测在非小细胞肺癌中的重要性成为个体化治疗药物研发的新里程碑-在特定的非小细胞肺癌人群中有显著的客观缓解率。 前不久，美国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安全和有效的治疗。” 接受Xalkori治疗病人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。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use XALKORI ® safely and effectively. See full prescribing information for XALKORI. XALKORI ® (crizotinib) capsules, for oral use Initial U.S. Approval: 2011 RECENT MAJOR CHANGES Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6) 9/2015 INDICATIONS AND USAGE XALKORI is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. (1) DOSAGE AND ADMINISTRATION Recommended dose: 250 mg orally, twice daily (2.2) Renal Impairment: 250 mg orally, once daily in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis. (2.2) DOSAGE FORMS AND STRENGTHS Capsules: 250 mg and 200 mg (3) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Hepatotoxicity: Fatal hepatotoxicity occurred in 0.1% of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.1) Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 2.9% of patients. Permanently discontinue in patients with ILD/pneumonitis. (5.2) QT Interval Prolongation: Occurred in 2.1% of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.3) Bradycardia: XALKORI can cause bradycardia. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue XALKORI. (5.4) Severe Visual Loss: Reported in 0.2% of patients. Discontinue XALKORI in patients with severe visual loss. Perform an ophthalmological evaluation. (5.5) Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. (5.6, 8.1, 8.3) ADVERSE REACTIONS The most common adverse reactions (≥25%) are vision disorders, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS CYP3A Inhibitors: Avoid concurrent use of XALKORI with strong CYP3A inhibitors. (7.1) CYP3A Inducers: Avoid concurrent use of XALKORI with strong CYP3A inducers. (7.2) CYP3A Substrates: Avoid concurrent use of XALKORI with CYP3A substrates with narrow therapeutic indices. (7.3) USE IN SPECIFIC POPULATIONS Lactation: Do not breastfeed while taking XALKORI (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 9/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of metastatic NSCLC with XALKORI based on the presence of ALK positivity in tumor specimens [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of ALK rearrangements in NSCLC is available at 2.2 Recommended Dosing The recommended dose of XALKORI is 250 mg orally, twice daily until disease progression or no longer tolerated by the patient. The recommended dose of XALKORI in patients with severe renal impairment (creatinine clearance <30 mL/min) not requiring dialysis is 250 mg orally, once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. If vomiting occurs after taking a dose of XALKORI, take the next dose at the regular time. 2.3 Dose Modification Reduce dose as below, if one or more dose reductions are necessary due to adverse reactions of Grade 3 or 4 severity, as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0: First dose reduction: XALKORI 200 mg taken orally twice daily Second dose reduction: XALKORI 250 mg taken orally once daily Permanently discontinue if unable to tolerate XALKORI 250 mg taken once daily Dose reduction guidelines are provided in Tables 1 and 2. Table 1. XALKORI Dose Modification – Hematologic Toxicities CTCAE Grade XALKORI Dosing Grade 3 Withhold until recovery to Grade 2 or less, then resume at the same dose schedule Grade 4 Withhold until recovery to Grade 2 or less, then resume at next lower dose Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). Table 2. XALKORI Dose Modification – Non-Hematologic Toxicities Criteria XALKORI Dosing Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 1.5 times ULN Withhold until recovery to baseline or less than or equal to 3 times ULN, then resume at reduced dose ALT or AST elevation greater than 3 times ULN with concurrent total bilirubin elevation greater than 1.5 times ULN (in the absence of cholestasis or hemolysis) Permanently discontinue Any Grade drug-related interstitial lung disease/pneumonitis Permanently discontinue QTc greater than 500 ms on at least 2 separate ECGs Withhold until recovery to baseline or to a QTc less than 481 ms, then resume at reduced dose QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia Permanently discontinue Bradycardia* (symptomatic, may be severe and medically significant, medical intervention indicated) Withhold until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above Evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at previous dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above If no contributing concomitant medication is identified, or if contributing concomitant medications are not discontinued or dose modified, resume at reduced dose upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above Bradycardia*,† (life-threatening consequences, urgent intervention indicated) Permanently discontinue if no contributing concomitant medication is identified If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume at 250 mg once daily upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring Visual Loss (Grade 4 Ocular Disorder) Discontinue during evaluation of severe vision loss Heart rate less than 60 beats per minute (bpm). Permanently discontinue for recurrence. Monitor complete blood counts including differential white blood cell counts monthly and as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. 3 DOSAGE FORMS AND STRENGTHS 250 mg capsules Hard gelatin capsule, size 0, pink opaque cap and body, with "Pfizer" on the cap and "CRZ 250" on the body. 200 mg capsules Hard gelatin capsule, size 1, white opaque body and pink opaque cap, with "Pfizer" on the cap and "CRZ 200" on the body. 4 CONTRAINDICATIONS None 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Drug-induced hepatotoxicity with fatal outcome occurred in 2 (0.1%) of the 1669 patients treated with XALKORI across clinical trials in patients with NSCLC. Concurrent elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to three times the upper limit of normal (ULN) and total bilirubin greater than or equal to two times the ULN, with normal alkaline phosphatase, occurred in 10 patients (0.6%) treated with XALKORI. Additionally, elevations in ALT or AST greater than five times the ULN occurred in 184 (11%) and 93 (5.7%) patients, respectively. Seventeen patients (1.0%) required permanent discontinuation due to elevated transaminases. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin every 2 weeks during the first 2 months of treatment, then 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 described in Table 2 [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.2 Interstitial Lung Disease (Pneumonitis) Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with XALKORI. Across clinical trials (n=1669), 49 XALKORI-treated patients (2.9%) had ILD of any grade, 18 patients (1.1%) had Grade 3 or 4 ILD, and 8 patients (0.5%) had fatal ILD. These cases generally occurred within 3 months after the initiation of XALKORI. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes of ILD/pneumonitis, and permanently discontinue XALKORI in patients diagnosed with drug-related ILD/pneumonitis [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.3 QT Interval Prolongation QTc prolongation can occur in patients treated with XALKORI. Across clinical trials, 32 of 1560 patients (2.1%) had QTcF (corrected QT by the Fridericia method) greater than or equal to 500 ms and 76 of 1520 patients (5.0%) had an increase from baseline QTcF greater than or equal to 60 ms by automated machine-read evaluation of ECG. 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 in patients who develop QTc greater than 500 ms or greater than or equal to 60 ms change from baseline with Torsade de pointes or polymorphic ventricular tachycardia or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc greater than 500 ms on at least 2 separate ECGs until recovery to a QTc less than or equal to 480 ms, then resume XALKORI at a reduced dose as described in Table 2 [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)]. 5.4 Bradycardia Symptomatic bradycardia can occur in patients receiving XALKORI. Across clinical trials, bradycardia occurred in 205 (12.3%) of 1669 patients treated with XALKORI. A total of 242 (14.9%) patients had a heart rate less than 50 beats per minute. In Studies 1 and 2, Grade 3 syncope occurred in 2.0% of XALKORI-treated patients and in 0.6% of the chemotherapy-treated patients. Avoid using XALKORI in combination with other agents known to cause bradycardia (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, clonidine and digoxin) to the extent possible. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, and if concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring [see Dosage and Administration (2.3) and Adverse Reactions (6)]. 5.5 Severe Visual Loss Across all clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (4/1669). Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation consisting of best corrected visual acuity, retinal photographs, visual fields, optical coherence tomography (OCT) and other evaluations as appropriate for new onset of severe visual loss. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume XALKORI should consider the potential benefits to the patient. 5.6 Embryofetal Toxicity Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those observed with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days following the final dose [see Use in Specific Populations (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] QT Interval Prolongation [see Warnings and Precautions (5.3)] Bradycardia [see Warnings and Precautions (5.4)] Severe Visual Loss [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of XALKORI is based primarily on 343 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily in two open-label, randomized, active-controlled trials (Studies 1 and 2). This is supplemented with information on adverse drug reactions in 1326 patients with ALK-positive metastatic NSCLC who received XALKORI 250 mg twice daily across clinical trials, for a total of 1669 patients across all clinical studies. The most common adverse reactions (≥25%) of XALKORI in Studies 1 and 2 are vision disorders, diarrhea, nausea, vomiting, constipation, edema, elevated transaminases, upper respiratory infection, decreased appetite, and dysgeusia. Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 The data in Table 3 are derived from 340 patients with ALK-positive metastatic NSCLC who had not received previous systemic treatment for advanced disease who received treatment in a randomized, multicenter, open-label, active-controlled trial (Study 1). Patients in the XALKORI arm (n=171) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 169 patients in the chemotherapy arm received pemetrexed 500 mg/m2 in combination with cisplatin 75 mg/m2 (n=91) or carboplatin at a dose calculated to produce an area under the concentration-time curve (AUC) of 5 or 6 mg∙min/mL (n=78). Chemotherapy was given by intravenous infusion every 3 weeks for up to 6 cycles, in the absence of dose-limiting chemotherapy-related toxicities. After 6 cycles, patients remained on study with no additional anticancer treatment, and tumor assessments continued until documented disease progression. The median duration of study treatment was 10.9 months for patients in the XALKORI arm and 4.1 months for patients in the chemotherapy arm. Median duration of treatment was 5.2 months for patients who received XALKORI after cross over from chemotherapy. Across the 340 patients who were treated in Study 1, the median age was 53 years; 16% of patients were older than 65 years. A total of 62% of patients were female and 46% were Asian. Serious adverse events were reported in 58 patients (34%) treated with XALKORI. The most frequent serious adverse events reported in patients treated with XALKORI were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Dose reductions due to adverse reactions were required in 6.4% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in these patients were nausea (1.8%) and elevated transaminases (1.8%). Permanent discontinuation of XALKORI treatment for adverse reactions was 8.2%. The most frequent adverse reactions that led to permanent discontinuation in XALKORI-treated patients were elevated transaminases (1.2%), hepatotoxicity (1.2%), and ILD (1.2%). Tables 3 and 4 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients. Table 3. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 1  Adverse Reaction XALKORI (N=171) Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin) (N=169) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) Cardiac Disorders   Electrocardiogram QT prolonged 6 2 2 0   Bradycardia* 14 1 1 0 Eye Disorders   Vision disorder† 71 1 10 0 Gastrointestinal Disorders   Vomiting 46 2 36 3   Diarrhea 61 2 13 1   Constipation 43 2 30 0   Dyspepsia 14 0 2 0   Dysphagia 10 1 2 1   Abdominal pain‡ 26 0 12 0 General Disorders and Administration Site Conditions   Edema§ 49 1 12 1   Pyrexia 19 0 11 1 Infections and Infestations   Upper respiratory infection 32 0 12 1 Investigations   Weight increased 8 1 2 0 Musculoskeletal and Connective Tissue Disorders   Pain in extremity 16 0 7 0   Muscle spasm 8 0 2 1 Nervous System Disorder   Dizziness# 18 0 10 1   Dysgeusia 26 0 5 0   Headache 22 1 15 0 Includes cases reported within the clustered terms: Bradycardia (Bradycardia, Sinus bradycardia) Vision Disorder (Diplopia, Photophobia, Photopsia, Visual acuity reduced, Vision blurred, Vitreous floaters, Visual impairment) Abdominal pain (Abdominal discomfort, Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness) Edema (Edema, Edema peripheral, Face edema, Generalised edema, Local swelling, Periorbital edema) Upper respiratory infection (Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection) Dizziness (Balance disorder, Dizziness, Dizziness postural, Presyncope)  Additional adverse reactions occurring at an overall incidence between 1% and 60% in patients treated with XALKORI included nausea (56%), decreased appetite (30%), fatigue (29%), neuropathy (21%; which included gait disturbance, hypoaesthesia, muscular weakness, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy, sensory disturbance), rash (11%), renal cyst (5%), ILD (1%; ILD, pneumonitis), and syncope (1%). Table 4. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients in Study 1  Laboratory Abnormality XALKORI Chemotherapy Any Grade (%) Grade 3/4 (%) Any Grade (%) Grade 3/4 (%) Hematology   Neutropenia 52 11 59 16   Lymphopenia 48 7 53 13 Chemistry   ALT elevation 79 15 33 2   AST elevation 66 8 28 1   Hypophosphatemia 32 10 21 6 Previously Treated ALK-Positive Metastatic NSCLC - Study 2 The data in Table 5 are derived from 343 patients with ALK-positive metastatic NSCLC enrolled in a randomized, multicenter, active-controlled, open-label trial (Study 2). Patients in the XALKORI arm (n=172) received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion every three weeks until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Patients in the chemotherapy arm received pemetrexed unless they had received pemetrexed as part of first-line or maintenance treatment. The median duration of study treatment was 7.1 months for patients who received XALKORI and 2.8 months for patients who received chemotherapy. Across the 347 patients who were randomized to study treatment (343 received at least one dose of study treatment), the median age was 50 years; 14% of patients were older than 65 years. A total of 56% of patients were female and 45% of patients were Asian. Serious adverse reactions were reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the chemotherapy arm. The most frequent serious adverse reactions reported in patients treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea (2.3%), and ILD (2.9%). Fatal adverse reactions in XALKORI-treated patients in Study 2 occurred in 9 (5%) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, ILD, respiratory failure and sepsis. Dose reductions due to adverse reactions were required in 16% of XALKORI-treated patients. The most frequent adverse reactions that led to dose reduction in the patients treated with XALKORI were alanine aminotransferase (ALT) elevation (7.6%) including some patients with concurrent aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia (2.3%). XALKORI was discontinued for adverse reactions in 15% of patients. The most frequent adverse reactions that led to discontinuation of XALKORI were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and pulmonary embolism (1.2%). Tables 5 and 6 summarize common adverse reactions and laboratory abnormalities in XALKORI-treated patients. Table 5. Adverse Reactions Reported at a Higher Incidence (≥5% Higher for All Grades or ≥2% Higher for Grades 3/4) with XALKORI than Chemotherapy in Study 2 Adverse Reaction XALKORI (N=172) Chemotherapy (Pemetrexed or Docetaxel) (N=171) All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%)   Nervous System Disorder   Dizziness* 22 1 8 0   Dysgeusia 26 0 9 0   Syncope 3 3 0 0 Eye Disorders   Vision disorder† 60 0 9 0 Cardiac Disorders   Electrocardiogram QT prolonged 5 3 0 0   Bradycardia‡ 5 0 0 0 Investigations   Weight decreased 10 1 4 0 Gastrointestinal Disorders   Vomiting 47 1 18 0   Nausea 55 1 37 1   Diarrhea 60 0 19 1   Constipation 42 2 23 0   Dyspepsia 8 0 3 0 Infections and Infestations   Upper respiratory infection§ 26 0 13 1 Respiratory, Thoracic and Mediastinal Disorders   Pulmonary embolism 6 5 2 2 General Disorders and Administration Site Conditions   Edema# 31 0 16 0 Includes cases reported within the clustered terms: Dizziness (Balance disorder, Dizziness, Dizziness postural) Vision Disorder (Diplopia, Photophobia, Photopsia, Vision blurred, Visual acuity reduced, Visual impairment, Vitreous floaters) Bradycardia (Bradycardia, Sinus bradycardia) Upper respiratory infection (Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Upper respiratory tract infection) Pulmonary embolism (Pulmonary artery thrombosis, Pulmonary embolism) Edema (Face edema, Generalized edema, Local swelling, Localized edema, Edema, Edema peripheral, Periorbital edema)  Additional adverse reactions occurring at an overall incidence between 1% and 30% in patients treated with XALKORI included (%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and hepatic failure (1%). Table 6. Summary of Treatment-Emergent Laboratory Abnormalities with Grade 3 or 4 Incidence of ≥4% in XALKORI-Treated Patients in Study 2 Laboratory Abnormality XALKORI Chemotherapy Any Grade (%) Grade 3/4 (%) Any Grade (%) Grade 3/4 (%) Hematology   Neutropenia 49 12 28 12   Lymphopenia 51 9 60 25 Chemistry   ALT elevation 76 17 38 4   AST elevation 61 9 33 0   Hypokalemia 18 4 10 1   Hypophosphatemia 28 5 25 6 Description of Selected Adverse Drug Reactions Vision disorders Vision disorders, most commonly visual impairment, photopsia, blurred vision, or vitreous floaters, occurred in 1038 (62%) of 1669 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. There were 13 (0.8%) patients with Grade 3 and 4 (0.2%) patients with Grade 4 visual impairment. Based on the Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with XALKORI in Studies 1 and 2 reported a higher incidence of visual disturbances compared to patients treated with chemotherapy. The onset of vision disorder generally was within the first week of drug administration. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4–7 days each week, lasted up to 1 minute, and had mild or no impact (scores 0 to 3 out of a maximum score of 10) on daily activities as captured in the VSAQ-ALK questionnaire. Neuropathy Neuropathy, most commonly sensory in nature, occurred in 419 (25%) of 1669 patients. Most events (95%) were Grade 1 or Grade 2 in severity. Renal Cysts Renal cysts were experienced by 50 (3%) of 1669 patients. Renal cysts occurred in 8 (5%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 1. Renal cysts occurred in 8 (5%) patients treated with XALKORI and 1 (1%) patient treated with chemotherapy in Study 2. The majority of renal cysts in XALKORI-treated patients were complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging characteristics suggestive of abscess formation. However, across clinical trials no renal abscesses were confirmed by microbiology tests. 7 DRUG INTERACTIONS 7.1 Drugs That May Increase Crizotinib Plasma Concentrations Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors. 7.2 Drugs That May Decrease Crizotinib Plasma Concentrations Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's Wort. 7.3 Drugs Whose Plasma Concentrations May Be Altered By Crizotinib Crizotinib inhibits CYP3A both in vitro and in vivo [see Clinical Pharmacology (12.3)]. Avoid concomitant use of CYP3A substrates with narrow therapeutic range, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus in patients taking XALKORI. If concomitant use of these CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, XALKORI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of XALKORI during pregnancy. In animal reproduction studies, oral administration of crizotinib in pregnant rats during organogenesis at exposures similar to those expected with the maximum recommended human dose resulted in embryotoxicity and fetotoxicity [see Data]. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Crizotinib was administered to pregnant rats and rabbits during organogenesis to study the effects on embryo-fetal development. Postimplantation loss was increased at doses ≥50 mg/kg/day (approximately 0.6 times the recommended human dose based on AUC) in rats. No teratogenic effects were observed in rats at doses up to the maternally toxic dose of 200 mg/kg/day (approximately 2.7 times the recommended human dose based on AUC) or in rabbits at doses of up to 60 mg/kg/day (approximately 1.6 times the recommended human dose based on AUC), though fetal body weights were reduced at these doses. 8.2 Lactation Risk Summary There is no information regarding the presence of crizotinib in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants do not breast feed during treatment with XALKORI and for 45 days after the final dose. 8.3 Females and Males of Reproductive Potential Contraception Females XALKORI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days after the final dose. Males Because of the potential for genotoxicty, advise males with females partners of reproductive potential to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Nonclinical Toxicology (13.1)]. Infertility Based on reproductive organ findings in animals, XALKORI may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of XALKORI in pediatric patients has not been established. Animal Data Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 5.4 times the recommended human dose based on AUC). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. 8.5 Geriatric Use Of the total number of patients in clinical studies of XALKORI (n=1669), 16% were 65 years or older and 3.7% were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. 8.6 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. Clinical studies excluded patients with AST or ALT greater than 2.5 × ULN, or greater than 5 × ULN, if due to liver metastases. Patients with total bilirubin greater than 1.5 × ULN were also excluded. Therefore, use caution in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60–89 mL/min) or moderate (CLcr 30–59 mL/min) renal impairment based on a population pharmacokinetic analysis. Increased exposure to crizotinib occurred in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. Administer XALKORI at a dose of 250 mg taken orally once daily in patients with severe renal impairment not requiring dialysis [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There have been no known cases of XALKORI overdose. There is no antidote for XALKORI. 11 DESCRIPTION XALKORI (crizotinib) is an oral receptor tyrosine kinase inhibitor. The molecular formula for crizotinib is C21H22Cl2FN5O. The molecular weight is 450.34 Daltons. Crizotinib is described chemically as (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine. The chemical structure of crizotinib is shown below: Crizotinib is a white to pale-yellow powder with a pKa of 9.4 (piperidinium cation) and 5.6 (pyridinium cation). The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from greater than 10 mg/mL to less than 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65. XALKORI capsules are supplied as printed hard-shell capsules containing 250 mg or 200 mg of crizotinib together with colloidal silicon dioxide, microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium starch glycolate, magnesium stearate, and hard gelatin capsule shells as inactive ingredients. The pink opaque capsule shell components contain gelatin, titanium dioxide, and red iron oxide. The white opaque capsule shell components contain gelatin, and titanium dioxide. The printing ink contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). 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 demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met. 12.2 Pharmacodynamics Cardiac Electrophysiology In an ECG sub-study conducted in 52 patients with ALK-positive NSCLC who received crizotinib 250 mg twice daily, the maximum mean QTcF (corrected QT by the Fridericia method) change from baseline was 12.3 msec (two-sided 90% upper CI: 19.5 msec). An exposure-QT analysis suggested a crizotinib plasma concentration dependent increase in QTcF [see Warnings and Precautions (5.3)]. 12.3 Pharmacokinetics Absorption Following a single oral dose, crizotinib was absorbed with median time to achieve peak concentration of 4 to 6 hours. Following crizotinib 250 mg twice daily, steady state was reached within 15 days and remained stable, with a median accumulation ratio of 4.8. Steady-state systemic exposure (Cmin and AUC) appeared to increase in a greater than dose proportional manner over the dose range of 200–300 mg twice daily. The mean absolute bioavailability of crizotinib was 43% (range: 32% to 66%) following a single 250 mg oral dose. A high-fat meal reduced crizotinib AUCinf and Cmax by approximately 14%. XALKORI can be administered with or without food [see Dosage and Administration (2.2)]. Distribution The geometric mean volume of distribution (Vss) of crizotinib was 1,772 L following intravenous administration of a 50 mg dose, indicating extensive distribution into tissues from the plasma. Binding of crizotinib to human plasma proteins in vitro is 91% and is independent of drug concentration. In vitro studies suggested that crizotinib is a substrate for P-glycoprotein (P-gp). The blood-to-plasma concentration ratio is approximately 1. Metabolism Crizotinib is predominantly metabolized by CYP3A4/5. The primary metabolic pathways in humans were oxidation of the piperidine ring to crizotinib lactam and O-dealkylation, with subsequent Phase 2 conjugation of O-dealkylated metabolites. Elimination Following single doses of crizotinib, the mean apparent plasma terminal half-life of crizotinib was 42 hours in patients. Following the administration of a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose was recovered in feces and urine, respectively. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. The mean apparent clearance (CL/F) of crizotinib was lower at steady state (60 L/h) after 250 mg twice daily than that after a single 250 mg oral dose (100 L/h), which was likely due to autoinhibition of CYP3A by crizotinib after multiple dosing. Drug interactions CYP3A inhibitors: Coadministration of a single 150 mg oral dose of crizotinib with ketoconazole (200 mg twice daily), a strong CYP3A inhibitor, increased crizotinib AUCinf and Cmax values by approximately 3.2-fold and 1.4-fold, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inhibitors on steady-state crizotinib exposure has not been evaluated [see Drug Interactions (7.1)]. CYP3A inducers: Coadministration of a single 250 mg oral dose of crizotinib with rifampin (600 mg once daily), a strong CYP3A inducer, decreased crizotinib AUCinf and Cmax by 82% and 69%, respectively, compared to crizotinib alone. However, the magnitude of effect of CYP3A inducers on steady-state crizotinib exposure has not been evaluated [see Drug Interactions (7.2)]. Gastric pH elevating medications: In healthy subjects, coadministration of a single 250 mg oral dose of crizotinib following administration of esomeprazole 40 mg daily for 5 days did not result in a clinically relevant change in crizotinib exposure (AUCinf decreased by 10% and no change in Cmax). CYP3A substrates: Coadministration of crizotinib (250 mg twice daily for 28 days) in patients increased the AUCinf of oral midazolam 3.7-fold compared to midazolam alone, suggesting that crizotinib is a moderate inhibitor of CYP3A [see Drug Interactions (7.3)]. Other CYP substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 are unlikely to occur. Crizotinib is an inhibitor of CYP2B6 in vitro. Therefore, crizotinib may increase plasma concentrations of coadministered drugs that are predominantly metabolized by CYP2B6. An in vitro study suggests that clinical drug-drug interactions as a result of crizotinib-mediated induction of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A are unlikely to occur. UGT substrates: In vitro studies suggest that clinical drug-drug interactions as a result of crizotinib-mediated inhibition of the metabolism of drugs that are substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9 or UGT2B7 are unlikely to occur. Substrates of transporters: Crizotinib inhibited P-glycoprotein (P-gp) in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of P-gp. Crizotinib inhibited the hepatic uptake transporter, organic cation transporter 1 (OCT1), and renal uptake transporter, organic cation transporter 2 (OCT2), in vitro at clinically relevant concentrations. Therefore, crizotinib has the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2. Crizotinib did not inhibit the human hepatic uptake transport proteins OATP1B1 or OATP1B3, or the renal uptake transport proteins OAT1 or OAT3 in vitro at clinically relevant concentrations. Effect on other transport proteins: Crizotinib did not inhibit the hepatic efflux bile salt export pump transporter (BSEP) in vitro at clinically relevant concentrations. Specific populations Hepatic Impairment: As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. However, XALKORI has not been studied in patients with hepatic impairment. Clinical studies excluded patients with ALT or AST greater than 2.5 × ULN or greater than 5 × ULN if due to liver metastases. Patients with total bilirubin greater than 1.5 × ULN were also excluded [see Use in Specific Populations (8.6)]. The population pharmacokinetic analysis using the data from approximately 1200 patients with cancer who received XALKORI suggested that baseline total bilirubin (0.1 to 2.1 mg/dL) or AST levels (7 to 124 U/L) did not have a clinically relevant effect on the exposure of crizotinib. Renal impairment: The pharmacokinetics of crizotinib were evaluated using the population pharmacokinetic analysis in patients with mild (CLcr 60–89 mL/min, N=433) and moderate (CLcr 30–59 mL/min, N=137) renal impairment. Mild or moderate renal impairment has no clinically relevant effect on the exposure of crizotinib. A study was conducted in 7 patients with severe renal impairment (CLcr <30 mL/min) who did not require dialysis and 8 patients with normal renal function (CLcr ≥90 mL/min). All patients received a single 250 mg oral dose of XALKORI. The mean AUCinf for crizotinib increased by 79% and the mean Cmax increased by 34% in patients with severe renal impairment compared to those with normal renal function. Similar changes in AUCinf and Cmax were observed for the active metabolite of crizotinib [see Dosage and Administration (2.2) and Use in Specific Populations (8.7)]. Ethnicity: No clinically relevant difference in the exposure of crizotinib between Asian patients (N=523) and non-Asian patients (N=691). Age: Age has no effect on the exposure of crizotinib based on the population pharmacokinetic analysis. Body weight and gender: No clinically relevant effect of body weight or gender on the exposure of crizotinib based on the population pharmacokinetic analysis. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with crizotinib have not been conducted. Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. No specific studies with crizotinib have been conducted in animals to evaluate the effect on fertility; however, crizotinib is considered to have the potential to impair reproductive function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given greater than or equal to 50 mg/kg/day for 28 days (greater than 1.7 times the recommended human dose based on AUC). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) for 3 days. 14 CLINICAL STUDIES Previously Untreated ALK-Positive Metastatic NSCLC - Study 1 The efficacy and safety of XALKORI for the treatment of patients with ALK-positive metastatic NSCLC, who had not received previous systemic treatment for advanced disease, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 1). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) as assessed by independent radiology review (IRR) committee. Additional efficacy outcome measures included objective response rate (ORR) as assessed by IRR, duration of response, and overall survival (OS). Patient-reported lung cancer symptoms were assessed at baseline and periodically during treatment. Patients were randomized to receive XALKORI (n=172) or chemotherapy (n=171). Randomization was stratified by ECOG performance status (0–1, 2), race (Asian, non-Asian), and brain metastases (present, absent). Patients in the XALKORI arm received XALKORI 250 mg orally twice daily until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 or carboplatin AUC of 5 or 6 mg∙min/mL by intravenous infusion every 3 weeks for up to 6 cycles. Patients in the chemotherapy arm were not permitted to receive maintenance chemotherapy. At the time of documented disease progression, as per independent radiology review, patients randomized to chemotherapy were offered XALKORI. The demographic characteristics of the overall study population were 62% female, median age of 53 years, baseline ECOG performance status 0 or 1 (95%), 51% White and 46% Asian, 4% current smokers, 32% past smokers, and 64% never smokers. The disease characteristics of the overall study population were metastatic disease in 98% of patients, 92% of patients' tumors were classified as adenocarcinoma histology, 27% of patients had brain metastases, and 7% received systemic chemotherapy as adjuvant or neoadjuvant therapy. Of those randomized to chemotherapy, 70% received XALKORI after IRR documented progression. Study 1 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. The OS analysis conducted at the time of the PFS analysis did not suggest a difference in survival between arms. Table 7 and Figure 1 summarize the efficacy results. Exploratory patient-reported symptom measures of baseline and post-treatment dyspnea, cough, and chest pain suggested a delay in time to development of or worsening of dyspnea, but not cough or chest pain, in patients treated with XALKORI as compared to chemotherapy. The patient-reported delay in onset or worsening of dyspnea may be an overestimation, because patients were not blinded to treatment assignment. Table 7. Previously Untreated ALK-Positive Metastatic NSCLC - Efficacy Results  XALKORI (N=172) Chemotherapy (N=171)   Progression-free Survival (Based on IRR)   Number of Events (%) 100 (58%) 137 (80%)     Progressive Disease 89 (52%) 132 (77%)     Death 11 (6%) 5 (3%)   Median, Months (95% CI) 10.9 (8.3, 13.9) 7.0 (6.8, 8.2)   HR (95% CI)* 0.45 (0.35, 0.60)   P-value† <0.001 Overall Survival‡   Number of Events (%) 44 (26%) 46 (27%)   Median, Months (95% CI) NR NR   HR (95% CI)* 0.82 (0.54,1.26)   P-value† 0.36 Tumor Responses (Based on IRR)   Objective Response Rate % (95% CI) 74% (67, 81) 45% (37, 53)     CR, n (%) 3 (1.7%) 2 (1.2%)     PR, n (%) 125 (73%) 75 (44%)   P-value§ <0.001 Duration of Response   Median, Months(95% CI) 11.3 (8.1, 13.8) 5.3 (4.1, 5.8) HR=Hazard Ratio; CI=confidence interval; IRR=Independent radiology review; NR=not reached; CR=complete response; PR=partial response. Based on the Cox proportional hazards stratified analysis. Based on the stratified Log-rank test. OS analysis was not adjusted for the potentially confounding effects of cross over. Based on the stratified Cochran-Mantel-Haenszel test. Estimated using the Kaplan Meier method.  Figure 1. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR Previously Treated ALK-Positive Metastatic NSCLC - Study 2 The efficacy and safety of XALKORI as monotherapy for the treatment of 347 patients with ALK-positive metastatic NSCLC, previously treated with one platinum-based chemotherapy regimen, was demonstrated in a randomized, multicenter, open-label, active-controlled study (Study 2). The major efficacy outcome was PFS as assessed by IRR. Additional efficacy outcomes included ORR as assessed by IRR, duration of response, and OS. Patients were randomized to receive XALKORI 250 mg orally twice daily (n=173) or chemotherapy (n=174). Chemotherapy consisted of pemetrexed 500 mg/m2 (if pemetrexed naïve; n=99) or docetaxel 75 mg/m2 (n=72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression, intolerance to therapy, or the investigator determined that the patient was no longer experiencing clinical benefit. Randomization was stratified by ECOG performance status (0–1, 2), brain metastases (present, absent), and prior EGFR tyrosine kinase inhibitor treatment (yes, no). Patients were required to have ALK-positive NSCLC as identified by the FDA-approved assay, Vysis ALK Break-Apart FISH Probe Kit, prior to randomization. A total of 112 (64%) patients randomized to the chemotherapy arm subsequently received XALKORI after disease progression. The demographic characteristics of the overall study population were 56% female, median age of 50 years, baseline ECOG performance status 0 or 1 (90%), 52% White and 45% Asian, 4% current smokers, 33% past smokers, and 63% never smokers. The disease characteristics of the overall study population were metastatic disease in at least 95% of patients and at least 93% of patients' tumors were classified as adenocarcinoma histology. Study 2 demonstrated a statistically significant improvement in PFS in the patients treated with XALKORI. Table 8 and Figure 2 summarize the efficacy results. Table 8. Previously Treated ALK-Positive Metastatic NSCLC - Efficacy Results  XALKORI (N=173) Chemotherapy (N=174)   Progression-free Survival (Based on IRR)   Number of Events (%) 100 (58%) 127 (73%)     Progressive Disease 84 (49%) 119 (68%)     Death 16 (9%) 8 (5%)   Median, Months (95% CI) 7.7 (6.0, 8.8) 3.0* (2.6, 4.3)   HR (95% CI)† 0.49 (0.37,0.64)   P-value‡ <0.001 Overall Survival§   Number of Events (%) 49 (28%) 47 (27%)   Median, Months (95% CI) 20.3 (18.1,NR) 22.8 (18.6,NR)   HR (95% CI)† 1.02 (0.68,1.54)   P-value‡ 0.92 Tumor Responses (Based on IRR)   Objective Response Rate % (95% CI) 65% (58, 72) 20% (14, 26)     CR, n (%) 1 (0.6%) 0     PR, n (%) 112 (65%) 34 (20%)   P-value <0.001 Duration of Response   Median, Months (95% CI) 7.4 (6.1, 9.7) 5.6 (3.4, 8.3) HR=Hazard Ratio; CI=confidence interval; IRR=Independent radiology review; NR=not reached; CR=complete response; PR=partial response. For pemetrexed, the median PFS was 4.2 months. For docetaxel, the median PFS was 2.6 months. Based on the Cox proportional hazards stratified analysis. Based on the stratified Log-rank test. Interim OS analysis conducted at 40% of total events required for final analysis. Based on the stratified Cochran-Mantel-Haenszel test. Figure 2. Kaplan-Meier Curves of Progression-Free Survival as Assessed by IRR in Study 2 16 HOW SUPPLIED/STORAGE AND HANDLING 250 mg capsules Hard gelatin capsule with pink opaque cap and body, printed with black ink "Pfizer" on the cap, "CRZ 250" on the body; available in: Bottles of 60 capsules:    NDC 0069-8140-20 200 mg capsules Hard gelatin capsule with pink opaque cap and white opaque body, printed with black ink "Pfizer" on the cap, "CRZ 200" on the body; available in: Bottles of 60 capsules:    NDC 0069-8141-20 Store at room temperature 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].  17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the symptoms of hepatotoxicity, and that they should be reported immediately [see Warnings and Precautions (5.1)]. Advise patients to immediately report any new or worsening pulmonary symptoms [see Warnings and Precautions (5.2)]. Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking XALKORI. Advise patients to report these symptoms and to inform their physician about the use of any heart or blood pressure medications [see Warnings and Precautions (5.4)]. Inform patients of the potential risk of severe visual loss and to immediately contact their physician if they develop severe visual loss. Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events and may occur while driving or operating machinery. The onset of visual disorders most commonly occurs during the first week of treatment [see Warnings and Precautions (5.5) and Adverse Reactions (6)]. Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received XALKORI. Nausea and vomiting began most commonly during the first few days of treatment [see Adverse Reactions (6)]. Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. Advise patients to take XALKORI with or without food and swallow XALKORI capsules whole. If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. If a patient vomits after taking a dose of XALKORI, advise the patient not to take an extra dose, but to take the next dose at the regular time. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with XALKORI and for at least 45 days after the final dose [see Use in Specific Populations (8.3)]. Advise females not to breastfeed during treatment with XALKORI and for 45 days after the final dose [see Use in Specific Populations (8.2)]. Advise females and males of reproductive potential of the potential for reduced fertility from XALKORI [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Advise male patients with female partners of reproductive potential to use condoms during treatment with XALKORI and for at least 90 days after the final dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7 美国FDA2011年8月26日为一种类型的晚期肺癌批准Xalkori(crizotinib)与伴诊断药盒 批准日期：2011年8月26日；公司：辉瑞Pfizer Inc. 美国食品药品监督管理局批准Xalkori(crizotinib)治疗某些晚期(局部晚期或转移)非小细胞肺癌表达异常变性淋巴瘤激酶基因的患者。 Xalkori正在与伴诊断检验被批准，检验将有助于确定患者是否有异常的ALK基因，一种一类基因检验的第一个被称为Vysis ALK Break Apart FISH Probe Kit。这是今年第二次批准的靶向治疗与一种检验。 这个ALK基因异常引起癌发生和生长。NSCLC约1%至7%有ALK基因异常。有这种形式肺癌患者典型地为非吸烟者。Xalkori作用通过阻断某些蛋白被称为激酶，包括异常ALK基因生成的蛋白。Xalkori是一种药丸作为单药治疗每天服用2次。 FDA药物评价和研究中心肿瘤药品办公室主任Richard Pazdur, M.D.说：“Xalkori与一种特异性检验的批准允许选择更可能对药物反应的患者”“靶向治疗例如Xalkori是为正在治疗这种疾病患者的重要选择和可能最终导致较少副作用。” 在两项多中心，单组研究纳入总共255例有晚期ALK-阳性NSCLC患者确定Xalkori的安全性和有效性。纳入研究前采集患者肺癌组织样品和为ALK基因异常检验。研究被设计测量客观反应率，经受完全或部分癌症皱缩患者的百分率。在本研究中大多数患者曾接受既往化疗。 在一项研究中，客观反应率为50%与中位反应时间42周。在另一项研究中，客观反应率为61%与中位反应时间48周。 FDA基于研究之一的资料批准Vysis ALK Break Apart FISH Probe药盒。 Xalkori是在FDA优先评审计划下审评，此计划提供一个加快6个月药物审评，可提供治疗中主要进展或当无存在的适当治疗时提供治疗。 Xalkori正在被FDA的加速批准计划批准，此计划允许监督管理局根据临床资料显示对严重疾病的终点的影响预计对患者临床效益而批准治疗药物。这计划设计提供患者更早得到鼓舞人新药，接着进一步研究证实药物的临床效益。 Xalkori和伴随Vysis ALK Break Apart FISH Probe 药盒在2011年9月提前批准， FDA审评目标日期和伴随诊断2011年9月28日，审评目标日期。 FDA的设备和放射学健康中心体外诊断设备评价和安全性办公室主任Alberto Gutierrez, Ph.D.,说：“肿瘤研究的趋势继续向靶向治疗，”“这个检验是伴诊断在决定最安全和最有效治疗及时输送给有严重和危及生命疾病患者生命起重要作用的一个实例。” 接受Xalkori患者最常报道副作用包括视力障碍，恶心，腹泻，呕吐，肿胀(水肿)，和便秘。视力障碍包括视力受损，光闪烁，视力模糊，飞蚊症，复视，对光敏感，和视野缺损。Xalkori使用还曾伴有肺组织炎症 (肺炎)，可能危及生命。有治疗-相关肺炎患者应永远停止用Xalkori治疗。妊娠妇女不应使用此药。 在2011年7月，FDA发出工业指导原则草案关于监督管理局对于评审伴随诊断和相应药物治疗的政策。为公众评议可得到这个指导原则。 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。