新型肺癌新药Alecensa (Alectinib Capsules)获美国FDA加速批准上市
近日，美国FDA批准Genentech的Alecensa（alectinib）用于治疗晚期（转移性） ALK-阳性非小细胞肺癌（NSCLC），患者病情已经恶化，或谁不能再容忍目前的治疗，称为Xalkori（crizotinib），该药为Pfizer生产的。
肺癌是癌症死亡的主力军，在美国2015年估计新增221,200病例，158,040会导致死亡。非小细胞肺癌是肺癌的最常见类型。ALK（间变性淋巴瘤激酶）基因突变可以发生在几个不同类型的癌症细胞，包括肺癌细胞。ALK基因突变目前占据5%左右的非小细胞肺癌患者的。在转移性癌中，这种疾病蔓延到身体的新部位。针对ALK阳性非小细胞肺癌的患者，大脑是疾病传播的常见的地方。
FDA的药物评价和研究中心血液学和肿瘤学办公室主任Richard Pazdur, M.D.，说：‘今天的批准为一些已有的治疗没有任何起效，如一旦他们的疾病不再对Xalkori有任何反应那组病人提供一种新疗法’。‘除了对肺肿瘤的主要影响外，Alecensa临床试验提供了对肿瘤已经扩散到大脑起到一定效应，这是非常重要的效果，对于临床医生来说’。
Alecensa是一种口服的药物，阻止ALK蛋白的活性，某种意义上可以阻止非小细胞肺癌细胞的生长和传播。
在两对临床试验中参与者均是对Xalkori治疗转移性ALK阳性非小细胞肺癌，不再起作用，此时患者服用Alecensa的疗效及安全性的研究。研究参与者收到 Alecensa 每日两次，测量其药物对肺肿瘤的影响。在第一对临床试验中，38%的参与者非小细胞肺癌肿瘤经历部分收缩的，这种效果持续了7.5个月（平均）。在第二对研究中，44%的参与者非小细胞肺癌肿瘤经历部分收缩的，这种效果持续了11.2个月（平均）。试验还审查了Alecensa?的影响个人的脑转移瘤，这在该病群体中是一个普遍现象。这两项试验中61%的参加者脑转移瘤经历完全或部分的减少，这种效果持续了9.1 个月（平均）。
Alecensa的最常见的副作用是疲劳，便秘，肿胀（水肿）和肌肉疼痛（肌痛）。Alecensa可能会导致严重的副作用，包括肝脏的问题，严重或危及生命的肺炎症、 心跳过缓和严重的肌肉问题。接受Alecensa治疗的患者暴露于阳光下，可能会导致晒伤。
批准日前：2015年12月11日：公司：Genentech
ALECENSA®(盐酸阿雷替尼 alectinib)胶囊，供口服使用

美国初次批准：2015
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ALECENSA safely and effectively. See full prescribing information for ALECENSA.
ALECENSA ® (alectinib) capsules, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
ALECENSA is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. (1)
DOSAGE AND ADMINISTRATION
600 mg orally twice daily. Administer ALECENSA with food. (2.1)
DOSAGE FORMS AND STRENGTHS
Capsules: 150 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Hepatotoxicity: Monitor liver laboratory tests every 2 weeks during the first 2 months of treatment, and then periodically during treatment. In case of severe ALT, AST, or bilirubin elevations, withhold, then reduce dose, or permanently discontinue ALECENSA. (2.2, 5.1)
Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 0.4% of patients. Immediately withhold ALECENSA in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis have been identified. (2.2, 5.2)
Bradycardia: Monitor heart rate and blood pressure regularly. If symptomatic, withhold ALECENSA then reduce dose, or permanently discontinue. (2.2, 5.3)
Severe Myalgia and Creatine Phosphokinase (CPK) Elevation: Occurred in 1.2% and 4.6% of patients, respectively. Assess CPK every 2 weeks during the first month of treatment and in patients reporting unexplained muscle pain, tenderness, or weakness. In case of severe CPK elevations, withhold, then resume or reduce dose. (2.2, 5.4)
Embryo-Fetal Toxicity: ALECENSA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.5, 8.1 8.3)
ADVERSE REACTIONS
The most common adverse reactions (incidence ≥20%) were fatigue, constipation, edema and myalgia. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 12/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ALECENSA is indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.
This indication is approved under accelerated approval based on tumor response rate and duration of response [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing and Administration
The recommended dose of ALECENSA is 600 mg orally twice daily with food [see Clinical Pharmacology (12.3)]. Administer ALECENSA until disease progression or unacceptable toxicity.
Do not open or dissolve the contents of the capsule.
If a dose of ALECENSA is missed or vomiting occurs after taking a dose of ALECENSA, take the next dose at the scheduled time.
2.2 Dose Modifications for Adverse Reactions
The dose reduction schedule for ALECENSA is provided in Table 1.
Table 1. ALECENSA Dose Reduction Schedule 

Dose reduction schedule	Dose level
Starting dose	600 mg taken orally twice daily
First dose reduction	450 mg taken orally twice daily
Second dose reduction	300 mg taken orally twice daily

Discontinue if patients are unable to tolerate the 300 mg twice daily dose.
Recommendations for dose modifications of ALECENSA in case of adverse reactions are provided in Table 2.
Table 2. ALECENSA Dose Modifications for Adverse Reactions 

Criteria*	ALECENSA Dose Modification
ALT or AST elevation of greater than 5 times upper limit of normal (ULN) with total bilirubin less than or equal to 2 times ULN	Temporarily withhold until recovery to baseline or to less than or equal to 3 times ULN, then resume at reduced dose as per Table 1.
ALT or AST elevation greater than 3 times ULN with total bilirubin elevation greater than 2 times ULN in the absence of cholestasis or hemolysis	Permanently discontinue ALECENSA.
Total bilirubin elevation of greater than 3 times ULN	Temporarily withhold until recovery to baseline or to less than or equal to 1.5 times ULN, then resume at reduced dose as per Table 1.
Any grade treatment-related interstitial lung disease (ILD)/pneumonitis	Permanently discontinue ALECENSA.
Symptomatic bradycardia	Withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above.
	If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume ALECENSA 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 ALECENSA at reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above.
Bradycardia† (life-threatening consequences, urgent intervention indicated)	Permanently discontinue ALECENSA if no contributing concomitant medication is identified.
	If contributing concomitant medication is identified and discontinued, or its dose is adjusted, resume ALECENSA at reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence.
CPK elevation greater than 5 times ULN	Temporarily withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at same dose.
CPK elevation greater than 10 times ULN or second occurrence of CPK elevation of greater than 5 times ULN	Temporarily withhold until recovery to baseline or to less than or equal to 2.5 times ULN, then resume at reduced dose as per Table 1.

ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal; ILD = interstitial lung disease; CPK = blood creatine phosphokinase
Heart rate less than 60 beats per minute (bpm)
3 DOSAGE FORMS AND STRENGTHS
150 mg hard capsules, white, with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body. 
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity
Elevations of AST greater than 5 times the upper limit of normal (ULN) occurred in 3.6% of patients, and elevations of ALT greater than 5 times the ULN occurred in 4.8% of patients. Elevations of bilirubin greater than 3 times the ULN occurred in 2.8% of patients. The majority (73% of the patients with hepatic transaminase elevations and 49% of the patients with bilirubin elevations) of these events occurred during the first 2 months of treatment. Four patients discontinued ALECENSA for Grade 3-4 AST and/or ALT elevations, and 3 patients discontinued ALECENSA for Grade 3 bilirubin elevations. Two patients with Grade 3-4 AST/ALT elevations had documented drug induced liver injury by liver biopsy.
Monitor liver function tests including ALT, AST, and total bilirubin every 2 weeks during the first 2 months of treatment, then periodically during treatment, with more frequent testing in patients who develop transaminase and bilirubin elevations. Based on the severity of the adverse drug reaction, withhold ALECENSA and resume at a reduced dose, or permanently discontinue ALECENSA as described in Table 2 [see Dosage and Administration (2.2)].
5.2 Interstitial Lung Disease (ILD)/Pneumonitis
Severe ILD (Grade 3) occurred in one (0.4%) of 253 patients exposed to ALECENSA in clinical trials.
Promptly investigate for ILD/pneumonitis in any patient who presents with worsening of respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough and fever).
Immediately withhold ALECENSA treatment in patients diagnosed with ILD/pneumonitis and permanently discontinue ALECENSA if no other potential causes of ILD/pneumonitis have been identified [see Dosage and Administration (2.2) and Adverse Reactions (6)].
5.3 Bradycardia
Symptomatic bradycardia can occur with ALECENSA. Cases of bradycardia (7.5%) have been reported in patients treated with ALECENSA. Twenty percent of 221 patients treated with ALECENSA for whom serial ECGs were available had heart rates of less than 50 beats per minute (bpm).
Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. In cases of symptomatic bradycardia that is not life-threatening, withhold ALECENSA until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above and evaluate concomitant medications known to cause bradycardia, as well as anti-hypertensive medications. If attributable to a concomitant medication, resume ALECENSA at a reduced dose (see Table 1) upon recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring as clinically indicated. Permanently discontinue ALECENSA in case of recurrence. Permanently discontinue ALECENSA in cases of life-threatening bradycardia if no contributing concomitant medication is identified [see Dosage and Administration (2.2)].
5.4 Severe Myalgia and Creatine Phosphokinase (CPK) Elevation
Myalgia or musculoskeletal pain occurred in 29% of patients in Study 1 and Study 2. The incidence of Grade 3 myalgia/musculoskeletal pain was 1.2%. Dose modifications for myalgia/musculoskeletal pain were required in 0.8% of patients.
Elevations of CPK occurred in 43% of 218 patients with CPK laboratory data available in Study 1 and Study 2. The incidence of Grade 3 elevations of CPK was 4.6%. Median time to Grade 3 CPK elevation was 14 days (interquartile range 13-14 days). Dose modifications for elevation of CPK occurred in 5.0% of patients.
Advise patients to report any unexplained muscle pain, tenderness, or weakness. Assess CPK levels every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, withhold ALECENSA, then resume or reduce dose [see Dosage and Administration (2.2)].
5.5 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to pregnant women. Administration of alectinib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans with alectinib 600 mg twice daily. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week following the final dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label:
Hepatotoxicity [see Warnings and Precautions (5.1)]
Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.2)]
Bradycardia [see Warnings and Precautions (5.3)]
Severe Myalgia and Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.4)]
Embryo-Fetal Toxicity [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 practice.
The safety of ALECENSA was evaluated in 253 patients with ALK-positive non-small cell lung cancer (NSCLC) treated with ALECENSA 600 mg orally twice daily in two clinical trials, Studies 1 and 2. The median duration of exposure to ALECENSA was 9.3 months. One hundred sixty-nine patients (67%) were exposed to ALECENSA for more than 6 months, and 100 patients (40%) for more than one year. The population characteristics were: median age 53 years, age less than 65 (86%), female (55%), White (74%), Asian (18%), NSCLC adenocarcinoma histology (96%), never or former smoker (98%), ECOG Performance Status (PS) 0 or 1 (91%), and prior chemotherapy treatment (78%).
Serious adverse reactions occurred in 19% of patients; the most frequently reported serious adverse reactions were pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%). Fatal adverse reactions occurred in 2.8% of patients and included hemorrhage (0.8%), intestinal perforation (0.4%), dyspnea (0.4%), pulmonary embolism (0.4%), and endocarditis (0.4%). Permanent discontinuation of ALECENSA for adverse reactions occurred in 6% of patients. The most frequent adverse reactions that led to permanent discontinuation were hyperbilirubinemia (1.6%), increased ALT levels (1.6%), and increased AST levels (1.2%). Overall, 23% of patients initiating treatment at the recommended dose required at least one dose reduction. The median time to first dose reduction was 48 days. The most frequent adverse reactions that led to dose reductions or interruptions were elevations in bilirubin (6%), CPK (4.3%), ALT (4.0%), and AST (2.8%), and vomiting (2.8%).
Table 3 summarizes adverse reactions in Studies 1 and 2.
Table 3. Adverse Reactions in ≥ 10% (All Grades) or ≥ 2% (Grade 3-4) of Patients in Studies 1 and 2 

Adverse Reactions	ALECENSA N=253
	All Grades (%)	Grades 3-4 (%)*
Fatigue †	41	1.2
Constipation	34	0
Edema ‡	30	0.8
Myalgia §	29	1.2
Cough	19	0
Rash	18	0.4
Nausea	18	0
Headache	17	0.8
Diarrhea	16	1.2
Dyspnea	16	3.6 #
Back pain	12	0
Vomiting	12	0.4
Increased weight	11	0.4
Vision disorder Þ	10	0

Per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Includes fatigue and asthenia.
Includes peripheral edema, edema, generalized edema, eyelid edema, and periorbital edema.
Includes myalgia and musculoskeletal pain.
Includes rash, maculopapular rash, acneiform dermatitis, erythema, generalized rash, papular rash, pruritic rash, and macular rash.
Includes one Grade 5 event
Includes blurred vision, vitreous floaters, visual impairment, reduced visual acuity, asthenopia, and diplopia.
Additional safety information from clinical trial experience
Photosensitivity occurred in 9.9% of patients exposed to ALECENSA in Studies 1 and 2. Patients were advised to avoid sun exposure and to use broad-spectrum sunscreen. The incidence of Grade 2 photosensitivity was 0.4%; the remaining events were Grade 1 in severity.
Table 4 summarizes laboratory abnormalities of ALECENSA in Studies 1 and 2.
Table 4. Laboratory Abnormalities Occurring in >20% of Patients in Studies 1 and 2 

Parameter	Alectinib N=250
	All Grades (%)	Grades 3-4 (%)*
Chemistry
Increased AST	51	3.6
Increased Alkaline Phosphatase	47	1.2
Increased CPK †	43	4.6
Hyperbilirubinemia	39	2.4
Hyperglycemia‡	36	2.0
Increased ALT	34	4.8
Hypocalcemia	32	0.4
Hypokalemia	29	4.0
Increased Creatinine §	28	0
Hypophosphatemia	21	2.8
Hyponatremia	20	2.0
Hematology
Anemia	56	2.0
Lymphopenia	22	4.6

Per CTCAE version 4.0
n=218 for CPK (with baseline values missing for 91 of these patients).
n=152 for fasting blood glucose (with baseline values missing for 5 of these patients).
Only patients with creatinine increases based on ULN definition.
n=217 for lymphocytes (with baseline values missing for 5 of these patients).
7 DRUG INTERACTIONS
No pharmacokinetic interactions with alectinib requiring dosage adjustment have been identified [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on animal studies and its mechanism of action, ALECENSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on ALECENSA use in pregnant women.
Administration of alectinib to pregnant rats and rabbits by oral gavage during the period of organogenesis resulted in embryo-fetal toxicity and abortion at maternally toxic doses with exposures approximately 2.7-times those observed in humans treated with alectinib at 600 mg twice daily [see Data]. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In a preliminary rabbit embryo-fetal study, administration of alectinib by oral gavage during the period of organogenesis resulted in abortion or complete embryo-fetal mortality at a maternally toxic dose of 27 mg/kg/day (approximately 2.9-fold the estimated area under the curve (AUC0-24h,ss) in humans treated with alectinib 600 mg BID) in three of six pregnant rabbits. The remaining three pregnant rabbits in this group had few live fetuses, decreased fetal and placental weights, and retroesophageal subclavian artery. In a rat preliminary embryo-fetal development study, administration of alectinib during organogenesis resulted in complete litter loss in all pregnant rats at 27 mg/kg/day (approximately 4.5-fold the estimated AUC0-24h,ss in humans treated with alectinib 600 mg BID). Doses greater than or equal to 9 mg/kg/day (approximately 2.7-fold the estimated human AUC0-24h,ss in humans treated with alectinib 600 mg BID), resulted in maternal toxicity as well as developmental toxicities including decreased fetal weight, dilated ureter, thymic cord, small ventricle and thin ventricle wall, and reduced number of sacral and caudal vertebrae.
8.2 Lactation
Risk Summary
There are no data on the presence of alectinib or its metabolites in human milk, the effects of alectinib on the breast-fed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants from alectinib, advise a lactating woman not to breastfeed during treatment with ALECENSA and for 1 week after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
ALECENSA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for 1 week after the final dose [see Use in Specific Populations (8.1)].
Males
Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 months following the final dose [see Non Clinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of ALECENSA in pediatric patients have not been established.
Animal Data
Juvenile animal studies have not been conducted using alectinib. In general toxicology studies, treatment of rats with doses of alectinib resulting in exposures greater than or equal to approximately 4.5 times those in humans treated with alectinib at 600 mg twice daily resulted in changes in the growing teeth and bones. Findings in teeth included discoloration and changes in tooth size along with histopathological disarrangement of the ameloblast and odontoblast layers. There were also decreases in the trabecular bone and increased osteoclast activity in the femur and sternum.
8.5 Geriatric Use
Clinical studies of ALECENSA did not include sufficient number of subjects aged 65 and older to determine whether they respond differently from younger subjects.
8.6 Renal Impairment
No dose adjustment is recommended for patients with mild or moderate renal impairment. The safety of ALECENSA in patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease has not been studied [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal (ULN) and aspartate transaminase (AST) greater than ULN or total bilirubin greater than 1.0 to 1.5 times ULN and any AST). The safety of ALECENSA in patients with moderate or severe hepatic impairment has not been studied [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
No experience with overdose is available. There is no specific antidote for overdose with ALECENSA. Alectinib and its major active metabolite M4 are > 99% bound to plasma proteins; therefore, hemodialysis is likely to be ineffective in the treatment of overdose.
11 DESCRIPTION
ALECENSA (alectinib) is a kinase inhibitor for oral administration. The molecular formula for alectinib is C30H34N4O2 ∙ HCl. The molecular weight is 482.62 g/mol (free base form) and 519.08 g/mol (hydrochloride salt). Alectinib is described chemically as 9-ethyl-6, 6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. The chemical structure of alectinib is shown below:

Alectinib HCl is a white to yellow white powder or powder with lumps with a pKa of 7.05 (base).
ALECENSA is supplied as hard capsules containing 150 mg of alectinib (equivalent to 161.33 mg alectinib HCl) and the following inactive ingredients: lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, and carboxymethylcellulose calcium. The capsule shell contains hypromellose, carrageenan, potassium chloride, titanium dioxide, corn starch, and carnauba wax. The printing ink contains red iron oxide (E172), yellow iron oxide (E172), FD&C Blue No. 2 aluminum lake (E132), carnauba wax, white shellac, and glyceryl monooleate.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Alectinib is a tyrosine kinase inhibitor that targets ALK and RET. In nonclinical studies, alectinib inhibited ALK phosphorylation and ALK-mediated activation of the downstream signaling proteins STAT3 and AKT, and decreased tumor cell viability in multiple cell lines harboring ALK fusions, amplifications, or activating mutations. The major active metabolite of alectinib, M4, showed similar in vitro potency and activity.
Alectinib and M4 demonstrated in vitro and in vivo activity against multiple mutant forms of the ALK enzyme, including some mutations identified in NSCLC tumors in patients who have progressed on crizotinib.
In mouse models implanted with tumors carrying ALK fusions, administration of alectinib resulted in antitumor activity and prolonged survival, including in mouse models implanted intracranially with ALK-driven tumor cell lines.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The ability of alectinib to prolong the QT interval was assessed in 221 patients administered ALECENSA 600 mg twice daily in clinical studies. ALECENSA did not prolong the QTc (QT corrected for heart rate) interval to any clinically relevant extent. One patient had a maximum post-baseline QTcF value of greater than 500 msec and one patient had a maximum QTcF change from baseline of greater than 60 msec.
12.3 Pharmacokinetics
The pharmacokinetics of alectinib and its major active metabolite M4 have been characterized in patients with ALK-positive NSCLC and healthy subjects.
In patients with ALK-positive NSCLC, the geometric mean (coefficient of variation %) steady-state maximal concentration (Cmax,ss) for alectinib was 665 ng/mL (44%) and for M4 was 246 ng/mL (45%) with peak to trough concentration ratio of 1.2. The geometric mean steady-state area under the curve from 0 to 12 hours (AUC0-12h,ss) for alectinib was 7,430 ng*h/mL (46%) and for M4 was 2,810 ng*h/mL (46%). Alectinib exposure is dose proportional across the dose range of 460 mg to 900 mg (i.e., 0.75 to 1.5 times the approved recommended dosage) under fed conditions. Alectinib and M4 reached steady-state concentrations by day 7. The geometric mean accumulation was approximately 6-fold for both alectinib and M4.
Absorption
Alectinib reached maximal concentrations at 4 hours following administration of ALECENSA 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC.
The absolute bioavailability of alectinib was 37% (90% CI: 34%, 40%) under fed conditions.
A high-fat, high-calorie meal increased the combined exposure (AUC0-inf) of alectinib plus M4 by 3.1-fold (90% CI: 2.7, 3.6) following oral administration of a single 600 mg dose of ALECENSA.
Distribution
The apparent volume of distribution is 4,016 L for alectinib and 10,093 L for M4.
Alectinib and M4 are bound to human plasma proteins greater than 99%, independent of drug concentration.
Alectinib concentrations in the cerebrospinal fluid in patients with ALK-positive NSCLC approximate estimated alectinib free concentrations in the plasma.
In vitro studies suggest that alectinib is not a substrate of P-glycoprotein (P-gp), but M4 is a substrate of P-gp. Alectinib and M4 are not substrates of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3.
Elimination
The apparent clearance (CL/F) is 81.9 L/hour for alectinib and 217 L/hour for M4. The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4 in patients with ALK-positive NSCLC.
Metabolism
Alectinib is metabolized by CYP3A4 to its major active metabolite M4. The geometric mean metabolite/parent exposure ratio at steady-state is 0.40. M4 is subsequently metabolized by CYP3A4. Alectinib and M4 were the main circulating moieties in plasma, constituting 76% of the total radioactivity.
Excretion
Ninety-eight percent of the radioactivity was excreted in feces following oral administration of a single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted in the feces as unchanged alectinib and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib. 
Specific Populations
Age, body weight, mild hepatic impairment, mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min), race (White, Asian, and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment, end-stage renal disease or moderate to severe hepatic impairment [see Use in Specific Populations (8.6, 8.7)].
Drug Interactions
Effect of Other Drugs on Alectinib
No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of ALECENSA with a strong CYP3A inhibitor (posaconazole), a strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole).
Effect of Alectinib on Other Drugs
No clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with ALECENSA.
In vitro studies suggest that alectinib and M4 do not inhibit CYP1A2, 2B6, 2C9, 2C19 or 2D6.
In vitro studies suggest that alectinib and M4 inhibit P-gp and BCRP. Alectinib did not inhibit OATP1B1, OATP1B3, OAT1, OAT3, or OCT2 transport activity in vitro.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with alectinib have not been conducted.
Alectinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay, but was positive with an increased number of micronuclei in a rat bone marrow micronucleus test. The mechanism of micronucleus induction was abnormal chromosome segregation (aneugenicity) and not a clastogenic effect on chromosomes.
No studies in animals have been performed to evaluate the effect of alectinib on fertility. No adverse effects on male and female reproductive organs were observed in general toxicology studies conducted in rats and monkeys.
14 CLINICAL STUDIES
The safety and efficacy of ALECENSA were established in two single-arm, multicenter clinical trials (Studies 1 and 2). Patients with locally advanced or metastatic ALK-positive NSCLC, who have progressed on crizotinib, with documented ALK positive NSCLC based on an FDA-approved test, and ECOG PS of 0-2 were enrolled in both studies. Eligibility criteria permitted enrollment of patients with prior chemotherapy and prior CNS radiotherapy provided that CNS metastases were stable for at least two weeks. All patients received ALECENSA 600 mg orally twice daily. The major efficacy outcome measure in both studies was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) as evaluated per Independent Review Committee (IRC). Additional outcome measures as evaluated by the IRC included duration of response (DOR), CNS ORR, and CNS DOR.
Study 1 was conducted in North America and enrolled 87 patients. Baseline demographic and disease characteristics in Study 1 were median age 54 years old (range 29 to 79, 18% 65 and over), 84% White and 8% Asian, 55% female, 35% ECOG PS 0 and 55% ECOG PS 1, 100% never or former smokers, 99% Stage IV, 94% adenocarcinoma, and 74% prior chemotherapy. The most common sites of extra-thoracic metastasis included 60% CNS (of whom 65% had received CNS radiation), 43% lymph nodes, 36% bone, and 34% liver.
Study 2 was conducted internationally and enrolled 138 patients. Baseline demographic and disease characteristics in Study 2 were median age 52 years old (range 22 to 79, 10% 65 and over), 67% White and 26% Asian, 56% female, 32% ECOG PS 0 and 59% ECOG PS 1, 98% never or former smokers, 99% Stage IV, 96% adenocarcinoma, and 80% prior chemotherapy. The most common sites of extra-thoracic metastasis included 61% CNS (of whom 73% had received CNS radiation), 51% bone, 38% lymph nodes, and 30% liver.
Efficacy results from Studies 1 and 2 in all treated patients are summarized in Table 5. The median duration of follow-up on Study 1 was 4.8 months for both IRC and Investigator assessments and on Study 2, 10.9 months for IRC assessment and 7.0 months for Investigator assessment. All responses were partial responses.
Table 5: Efficacy Results in Studies 1 and 2

Efficacy Parameter	Study 1 (N=87)		Study 2 (N=138)
	IRC* Assessment	Investigator Assessment	IRC* Assessment	Investigator Assessment
Objective Response Rate (95% CI)	38% (28; 49)	46% (35; 57)	44% (36; 53)	48% (39; 57)
Number of Responders	33	40	61	66
Duration of Response, median in months (95% CI)	7.5 (4.9, Not Estimable)	NE (4.9, Not Estimable)	11.2 (9.6, Not Estimable)	7.8 (7.4, 9.2)

18 patients in Study 1 and 16 patients in Study 2 did not have measurable disease at baseline as per IRC assessment and were classified as non-responders in the IRC analysis.
An assessment of ORR and duration of response for CNS metastases in the subgroup of 51 patients in Studies 1 and 2 with baseline measurable lesions in the CNS according to RECIST v1.1 are summarized in Table 6. Thirty-five (69%) patients with measurable CNS lesions had received prior brain radiation, including 25 (49%) who completed radiation treatment at least 6 months before starting treatment with ALECENSA. Responses were observed irrespective of prior brain radiation status.
Table 6: CNS Objective Response in Patients with Measurable CNS Lesions in Studies 1 and 2

Efficacy Parameter	N=51
CNS Objective Response Rate (95% CI)	61% (46, 74)
Complete Response	18%
Partial Response	43%
CNS Duration of Response, median in months (95% CI)	9.1 (5.8, not evaluable)

16 HOW SUPPLIED/STORAGE AND HANDLING
Hard capsules, white 150 mg capsules with "ALE" printed in black ink on the cap and "150 mg" printed in black ink on the body, available in:
240 capsules per bottle: NDC 50242-130-01
Storage and stability: Do not store above 30°C (86°F). Store in the original container to protect from light and moisture.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Inform patients of the following:
Hepatotoxicity
Inform patients of the signs and symptoms of bilirubin and hepatic transaminase elevations. Advise patients to contact their healthcare provider immediately for signs or symptoms of bilirubin and hepatic transaminase elevations [see Warnings and Precautions (5.1)].
Interstitial Lung Disease (ILD)/Pneumonitis
Inform patients of the risks of severe ILD/pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].
Bradycardia
Inform patients that symptoms of bradycardia including dizziness, lightheadedness, and syncope can occur while taking ALECENSA. Advise patients to contact their healthcare provider to report these symptoms and to inform their healthcare provider about the use of any heart or blood pressure medications [see Warnings and Precautions (5.3)].
Severe Myalgia/CPK elevation
Inform patients of signs and symptoms of myalgia, including unexplained and/or persistent muscle pain, tenderness, or weakness. Advise patients to contact their healthcare provider immediately to report new or worsening symptoms of muscle pain or weakness [see Warnings and Precautions (5.4)].
Photosensitivity
Inform patients of the signs and symptoms of photosensitivity. Advise patients to avoid prolonged sun exposure while taking ALECENSA and for at least 7 days after study drug discontinuation and to use proper protection from the sun. Advise patients to use a broad spectrum ultraviolet A (UVA)/ultraviolet B (UVB) sunscreen and lip balm (SPF ≥50) to help protect against potential sunburn [see Adverse Reactions (6.1)].
Embryo-Fetal Toxicity
ALECENSA can cause fetal harm if taken during pregnancy. Advise a pregnant woman of the potential risk to a fetus [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment with ALECENSA and for at least 1 week after the last dose of ALECENSA. Advise patients to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1, 8.3)].
Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ALECENSA and for 3 months after the last dose [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Lactation
Advise women not to breastfeed during treatment with ALECENSA and for one week after the last dose [see Use in Specific Populations (8.2)].
Administration
Instruct patients to take ALECENSA twice a day. Advise patients to take ALECENSA with food and to swallow ALECENSA capsules whole [see Dosage and Administration (2.1)].
Missed Dose
Advise patients that if a dose of ALECENSA is missed or if the patient vomits after taking a dose of ALECENSA, patients should be advised not to take an extra dose, but to take the next dose at the regular time [see Dosage and Administration (2.1)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=42c49deb-713b-427a-9670-08af08adcffb