新型抗癌药丸Tagrisso(osimertinib/AZD9291 中文药名：塔格瑞斯)获FDA批准上市
——新诊断测试鉴定被新药靶向的特异性基因突变
2015年11月13日，口服新药Tagrisso 塔格瑞斯（Osimertinib）获FDA加速批准，用于治疗晚期非小细胞肺癌（NSCLC）患者。Tagrisso用于治疗携带特定表皮生长因子受体（EGFR）突变（T790M）非小细胞肺癌，这种疾病在接受其他EGFR抑制剂后恶化。
根据美国国家癌症研究所报道，在美国肺癌是癌症死亡的主要原因，估计2015年美国有新增肺癌病例221,200名，158,040名肺癌患者死亡。非小细胞肺癌（NSCLC）是最常见的肺癌类型，当肺组织中形成癌细胞时，就会发生非小细胞肺癌，而EGFR基因是参与癌细胞的生长和扩散的蛋白质。
FDA药品评价与研究中心主任血液与肿瘤药品医学博士Richard Pazdur说“我们对肺癌的分子学基础以及肺癌对既往治疗产生耐药的原因有了更深刻的认识，本批准为耐药EGFR T790M突变阳性的非小细胞肺癌患者提供了一种新的治疗。根据大量的临床试验，Tagrisso使一半以上患者的肿瘤显著缩小”。
如今，FDA还批准了第一个护理诊断测试（cobaseGFR突变试验v2）以检测靶向耐药性EGFR突变。测试的新批版本（V2）由原始检测的cobaseGFR突变试验（V1）增加T790M突变的检测。
FDA医疗器械和放射健康中心的体外诊断和放射健康办公室主任Alberto Gutierrez博士称“批准安全、有效的护理诊断测试和药品，仍然是在肿瘤学领域重要的进展，cobaseGFR突变试验v2可用于检测EGFR基因突变，使治疗更有效。”
Tagrisso塔格瑞斯 的安全性和有效性是通过两个多中心的论证和单臂研究证实。共有411名患有EGFR T790M突变阳性的的晚期非小细胞肺癌，这些患者在接受EGFR阻断剂后疾病均恶化。在接受Tagrisso治疗后， 第一项研究中的57％的患者和第二项研究中的61％患者获得肿瘤完全消除或部分缩小（被称为客观缓解率）。
Tagrisso塔格瑞斯 的最常见的副作用是腹泻、皮肤干燥、皮疹、指甲感染或红肿。Tagrisso也可能会导致严重的副作用，包括肺部炎症和心脏损伤。它也可能伤害发育中的胎儿。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TAGRISSO safely and effectively. See full prescribing information for TAGRISSO.
TAGRISSO™ (osimertinib) tablet, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE
TAGRISSO is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. (1)
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
• Confirm the presence of T790M mutation in tumor specimens prior to initiation of treatment with TAGRISSO. ( 2.1)
• 80 mg orally once daily, with or without food. ( 2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 80 mg and 40 mg (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
• Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 3.3% of patients. Permanently discontinue TAGRISSO in patients diagnosed with ILD/Pneumonitis. ( 5.1)
• QTc Interval Prolongation: Monitor electrocardiograms and electrolytes in patients who have a history or predisposition for QTc prolongation, or those who are taking medications that are known to prolong the QTc interval. Withhold then restart at a reduced dose or permanently discontinue TAGRISSO. ( 2.4, 5.2)
• Cardiomyopathy: Occurred in 1.4% of patients. Assess left ventricular ejection fraction (LVEF) before treatment and then every 3 months thereafter. ( 2.4, 5.3)
• Embryo-Fetal Toxicity: TAGRISSO can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with TAGRISSO and for 6 weeks after final dose. Advise males to use effective contraception for 4 months, after the last dose of TAGRISSO. ( 5.3, 8.1, 8.3)
ADVERSE REACTIONS
Most common adverse reactions (≥25%) were diarrhea, rash, dry skin, and nail toxicity. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or www.TAGRISSO.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
• Strong CYP3A Inhibitors: Avoid concurrent administration with TAGRISSO if possible. If no alternative exists, the patient should be closely monitored for signs of toxicity. ( 7.1)
• Strong CYP3A Inducers: Avoid if possible because concomitant use may decrease osimertinib plasma concentrations. ( 7.1)
USE IN SPECIFIC POPULATIONS
Lactation: Do not breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 11/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
TAGRISSO is indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.
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 confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Confirm the presence of a T790M EGFR mutation in tumor specimens prior to initiation of treatment with TAGRISSO [see Indications and Usage (1) and Clinical Studies (14)]. Information on FDA-approved tests for the detection of T790M mutations is available at http://www.fda.gov/companiondiagnostics.
2.2 Recommended Dosage Regimen
The recommended dose of TAGRISSO is 80 mg tablet once a day until disease progression or unacceptable toxicity. TAGRISSO can be taken with or without food.
If a dose of TAGRISSO is missed, do not make up the missed dose and take the next dose as scheduled.
2.3 Administration to Patients Who Have Difficulty Swallowing Solids
Disperse tablet in 4 tablespoons (approximately 50 mL) of non-carbonated water only. Stir until tablet is completely dispersed and swallow or administer through naso-gastric tube immediately. Do not crush, heat, or ultrasonicate during preparation. Rinse the container with 4 to 8 ounces of water and immediately drink or administer through the naso-gastric tube [see Clinical Pharmacology (12.3)].
2.4 Dose Modification for Adverse Reactions
Table 1 Recommended Dose Modifications for TAGRISSO

Target Organ	Adverse Reactiona	Dose Modification
Pulmonary	Interstitial lung disease (ILD)/Pneumonitis	Permanently discontinue TAGRISSO.
Cardiac	QTc† interval greater than 500 msec on at least 2 separate ECGsb	Withhold TAGRISSO until QTc interval is less than 481 msec or recovery to baseline if baseline QTc is greater than or equal to 481 msec, then resume at 40 mg dose.
	QTc interval prolongation with signs/symptoms of life threatening arrhythmia	Permanently discontinue TAGRISSO.
	Asymptomatic, absolute decrease in LVEFc of 10% from baseline and below 50%	Withhold TAGRISSO for up to 4 weeks. • If improved to baseline LVEF, resume. • If not improved to baseline, permanently discontinue.
	Symptomatic congestive heart failure	Permanently discontinue TAGRISSO.
Other	Grade 3 or higher adverse reaction	Withhold TAGRISSO for up to 3 weeks.
	If improvement to Grade 0-2 within 3 weeks	Resume at 80 mg or 40 mg daily.
	If no improvement within 3 weeks	Permanently discontinue TAGRISSO.
a Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0). b ECGs = Electrocardiograms c LVEF = Left Ventricular Ejection Fraction QTc = QT interval corrected for heart rate

3 DOSAGE FORMS AND STRENGTHS
80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse.
40 mg tablets: beige, round and biconvex tablet marked with “AZ 40” on one side and plain on the reverse.
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS
5.1 Interstitial Lung Disease/Pneumonitis
Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.3% (n=27) of TAGRISSO treated patients (n=813); 0.5% (n=4) were fatal.
Withhold TAGRISSO and promptly investigate for ILD in any patient who presents with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed [see Dosage and Administration (2.4) and Adverse Reactions (6)].
5.2 QTc Interval Prolongation
The heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 411 patients in Study 1 and Study 2, one patient (0.2%) was found to have a QTc greater than 500 msec, and 11 patients (2.7%) had an increase from baseline QTc greater than 60 msec [see Clinical Pharmacology (12.2)].
In Study 1 and 2, patients with baseline QTc of 470 msec or greater were excluded. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life threatening arrhythmia [see Dosage and Administration (2.4)].
5.3 Cardiomyopathy
Across clinical trials, cardiomyopathy (defined as cardiac failure, pulmonary edema, ejection fraction decreased or stress cardiomyopathy) occurred in 1.4% (n=11) of TAGRISSO treated patients (n=813); 0.2% (n=2) were fatal.
In Study 1 and Study 2, Left Ventricular Ejection Fraction (LVEF) decline >10% and a drop to <50% occurred in 2.4% (9/375) of patients who had baseline and at least one follow up LVEF assessment.
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAGRISSO and then at 3 month intervals while on treatment. Withhold treatment with TAGRISSO if ejection fraction decreases by 10% from pretreatment values and is less than 50%. For symptomatic congestive heart failure or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].
5.4 Embryo-Fetal Toxicity
Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended human dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5-times those observed in patients at the 80 mg dose level.
Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose [see Use in Specific Populations (8.1), (8.3) and Clinical Pharmacology (12.3)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1)]
QTc Interval Prolongation [see Warnings and Precautions (5.2)]
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 data described below reflect exposure to TAGRISSO (80 mg daily) in 411 patients with EGFR T790M mutation-positive non-small cell lung cancer who received prior EGFR TKI therapy, in two single arm studies, Study 1 and Study 2. Patients with a past medical history of ILD or radiation pneumonitis that required steroid treatment, serious arrhythmia or baseline QTc interval greater than 470 ms were excluded from Study 1 and Study 2. Baseline patient and disease characteristics were: median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%), metastatic (96%), sites of brain metastases (39%), World Health Organization (WHO) performance status of 0 (37%) or 1 (63%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve (31%)], 2 or more prior lines of therapy (69%). Of the 411 patients, 333 patients were exposed to TAGRISSO for at least 6 months; 97 patients were exposed for at least 9 months; however no patient was exposed to TAGRISSO for 12 months.
In Studies 1 and 2, the most common (>20%) adverse reactions (all grades) observed in TAGRISSO-treated patients were diarrhea (42%), rash (41%), dry skin (31%), and nail toxicity (25%). Dose reductions occurred in 4.4% of patients treated with TAGRISSO. The most frequent adverse reactions that led to dose reductions or interruptions were: electrocardiogram QTc prolonged (2.2%) and neutropenia (1.9%). Serious adverse reactions reported in 2% or more patients were pneumonia and pulmonary embolus. There were 4 patients (1%) treated with TAGRISSO who developed fatal adverse reactions of ILD/pneumonitis. Other fatal adverse reactions occurring in more than 1 patient included pneumonia (4 patients) and CVA/cerebral hemorrhage (2 patients). Discontinuation of therapy due to adverse reactions occurred in 5.6% of patients treated with TAGRISSO. The most frequent adverse reactions that led to discontinuation were ILD/pneumonitis and cerebrovascular accidents/infarctions.
Tables 2 and 3 summarize the common adverse reactions and laboratory abnormalities observed in TAGRISSO-treated patients.
Table 2 Adverse Reactions (>10% for all NCI CTCAE* Grades or >2% for Grades 3-4) in Study 1 and Study 2 

Adverse Reaction	TAGRISSO N=411
	All Grades	Grade 3-4f
	%	%
Gastrointestinal disorders
Diarrhea	42	1.0
Nausea	17	0.5
Decreased appetite	16	0.7
Constipation	15	0.2
Stomatitis	12	0
Skin disorders
Rash a	41	0.5
Dry skin b	31	0
Nail toxicity c	25	0
Pruritus	14	0
Eye Disordersd	18	0.2
Respiratory
Cough	14	0.2
General
Fatigue	14	0.5
Musculoskeletal
Back pain	13	0.7
Central Nervous System
Headache	10	0.2
Infections
Pneumonia	4	2.2
Vascular events
Venous thromboembolism e	7	2.4

NCI CTCAE v4.0.
a Includes cases reported within the clustered terms for rash adverse events: Rash, rash generalized, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular, erythema, folliculitis, acne, dermatitis and acneform dermatitis.
b Includes dry skin, eczema, skin fissures, xerosis.
c Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail discoloration, nail disorder, nail dystrophy, nail infection, nail ridging, onychoclasis, onycholysis, onychomadesis, paronychia.
d Includes dry eye, vision blurred, keratitis, cataract, eye irritation, blepharitis, eye pain, lacrimation increased, vitreous floaters. Other ocular toxicities occurred in <1% of patients.
e Includes deep vein thrombosis, jugular venous thrombosis, and pulmonary embolism.
f No grade 4 events have been reported.
Additional clinically significant adverse reactions occurring in 2% or more of patients treated with TAGRISSO included cerebrovascular accident (2.7%).
Table 3 Common Laboratory Abnormalities (>20% for all NCI CTCAE Grades) in Study 1 and Study 2 

Laboratory Abnormality	TAGRISSO N=411
	Change from Baseline All Grades (%)	Change from Baseline to Grade 3 or Grade 4 (%)a
Clinical Chemistry
Hyponatremia	26	3.4
Hypermagnesemia	20	0.7
Hematologic
Lymphopenia	63	3.3
Thrombocytopenia	54	1.2a
Anemia	44	0.2
Neutropenia	33	3.4

a The only grade 4 laboratory abnormality was 1 patient with grade 4 thrombocytopenia
7 DRUG INTERACTIONS
Drug interaction studies with inhibitors, inducers or substrates of CYP enzymes and transporters have not been conducted with TAGRISSO.
7.1 Effect of Other Drugs on Osimertinib
Strong CYP3A Inhibitors
Avoid concomitant administration of TAGRISSO with strong CYP3A inhibitors, including macrolide antibiotics (e.g., telithromycin), antifungals (e.g., itraconazole), antivirals (e.g., ritonavir), nefazodone, as concomitant use of strong CYP3A inhibitors may increase osimertinib plasma concentrations. If no other alternative exists, monitor patients more closely for adverse reactions of TAGRISSO [see Dosage and Administrations (2.4) and Clinical Pharmacology (12.3)].
Strong CYP3A Inducers
Avoid concomitant administration of TAGRISSO with strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) as strong CYP3A inducers may decrease osimertinib plasma concentrations [see Clinical Pharmacology (12.3)].
7.2 Effect of Osimertinib on Other Drugs
Avoid concomitant administration of TAGRISSO with drugs that are sensitive substrates of CYP3A, breast cancer resistance protein (BCRP), or CYP1A2 with narrow therapeutic indices, including but not limited to fentanyl, cyclosporine, quinidine, ergot alkaloids, phenytoin, carbamazepine, as osimertinib may increase or decrease plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. There are no available data on TAGRISSO use in pregnant women. Administration of osimertinib to pregnant rats was associated with embryolethality and reduced fetal growth at plasma exposures 1.5 times the exposure at the recommended human dose [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
When administered to pregnant rats prior to embryonic implantation through the end of organogenesis (gestation days 2-20) at a dose of 20 mg/kg/day, which produced plasma exposures of approximately 1.5 times the clinical exposure, osimertinib caused post-implantation loss and early embryonic death. When administered to pregnant rats from implantation through the closure of the hard palate (gestation days 6 to 16) at doses of 1 mg/kg/day and above (0.1-times the AUC observed in patients at the recommended dose of 80 mg), an equivocal increase in the rate of fetal malformations and variations was observed in treated litters relative to those of concurrent controls. When administered to pregnant dams at doses of 30 mg/kg/day during organogenesis through lactation Day 6, osimertinib caused an increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day, osimertinib administration during the same period resulted in increased postnatal death as well as a slight reduction in mean pup weight at birth that increased in magnitude between lactation days 4 and 6.
8.2 Lactation
Risk Summary
There are no data on the presence of osimertinib in human milk, the effects of osimertinib on the breastfed infant or on milk production. Administration to rats during gestation and early lactation was associated with adverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1)]. Because of the potential for serious adverse reactions in breastfed infants from osimertinib, advise a lactating woman not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.1)].
Males
Advise male patients with female partners of reproductive potential to use effective contraception during and for 4 months following the final dose of TAGRISSO [see Nonclinical Toxicology (13.1)].
Infertility
Based on animal studies, TAGRISSO may impair fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness of TAGRISSO in pediatric patients have not been established.
8.5 Geriatric Use
One hundred eighty-seven (45%) of the 411 patients in clinical trials of TAGRISSO were 65 years of age and older, and 54 patients (13%) were 75 years of age and older. No overall differences in effectiveness were observed based on age. Exploratory analysis suggest a higher incidence of Grade 3 and 4 adverse reactions (32% versus 25%) and more frequent dose modifications for adverse reactions (23% versus 17%) in patients 65 years or older as compared to those younger than 65 years.
8.6 Renal Impairment
No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of osimertinib. Based on population pharmacokinetic analysis, no dose adjustment is recommended in patients with mild [creatinine clearance (CLcr) 60-89 mL/min] or moderate (CLcr 30-59 mL/min) renal impairment. There is no recommended dose of TAGRISSO for patients with severe renal impairment (CLcr <30 mL/min) or end-stage-renal disease [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of osimertinib. Based on population pharmacokinetic (PK) analysis, no dose adjustment is recommended in patients with mild hepatic impairment [total bilirubin <upper limit of normal (ULN) and AST between 1 to 1.5 times ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST]. There is no recommended dose for TAGRISSO for patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3)].
11 DESCRIPTION
Osimertinib is a kinase inhibitor for oral administration. The molecular formula for osimertinib mesylate is C28H33N7O2•CH4O3S, and the molecular weight is 596 g/mol. The chemical name is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt. Osimertinib has the following structural formula (as osimertinib mesylate):

TAGRISSO tablets contain 40 or 80 mg of osimertinib, equivalent to 47.7 and 95.4 mg of osimertinib mesylate, respectively. Inactive ingredients in the tablet core are mannitol, microcrystalline cellulose, low-substituted hydroxpropyl cellulose and sodium stearyl fumarate. The tablet coating consists of polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, ferric oxide yellow, ferric oxide red and ferric oxide black.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Osimertinib is kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) at approximately 9-fold lower concentrations than wild-type. In cultured cells and animal tumor implantation models, osimertinib exhibited anti-tumor activity against NSCLC lines harboring EGFR-mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-type EGFR amplifications. Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating at approximately 10% of the parent) with similar inhibitory profiles to osimertinib have been identified in the plasma after oral administration of osimertinib. AZ7550 showed a similar potency to osimertinib, while AZ5104 showed greater potency against exon 19 deletion and T790M mutants (approximately 8-fold) and wild-type (approximately 15-fold) EGFR. In vitro, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1, and BLK at clinically relevant concentrations.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The QTc interval prolongation potential of osimertinib was assessed in 210 patients who received TAGRISSO 80 mg daily in Study 2. A central tendency analysis of the QTcF data at steady-state demonstrated that the maximum mean change from baseline was 16.2 (upper bound of two-sided 90% confidence interval (CI) 17.6) msec. A pharmacokinetic/pharmacodynamic analysis in Study 2 suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg.
12.3 Pharmacokinetics
The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of osimertinib increased dose proportionally over 20 to 240 mg dose range (i.e., 0.25 to 3 times the recommended dosage) after oral administration and exhibited linear pharmacokinetics (PK). Administration of TAGRISSO orally once daily resulted in approximately 3-fold accumulation with steady state exposures achieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimal concentration) ratio was 1.6-fold.
Absorption
The median time to Cmax of osimertinib was 6 hours (range 3-24 hours).
Following administration of a 20 mg TAGRISSO tablets with a high-fat, high-calorie meal (containing approximately 58 grams of fat and 1000 calories), the Cmax and AUC of osimertinib increased by 14% and 19% respectively, compared to fasting conditions.
Distribution
The mean volume of distribution at steady-state (Vss/F) of osimertinib was 986 L. Plasma protein binding of osimertinib is likely high based on its physiochemical properties.
Elimination
Osimertinib plasma concentrations decreased with time and a population estimated mean half-life of osimertinib was 48 hours, and oral clearance (CL/F) was 14.2 (L/h).
Metabolism
The main metabolic pathways of osimertinib were oxidation (predominantly CYP3A) and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 and AZ5104) have been identified in the plasma after TAGRISSO oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state.
Excretion
Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination.
Specific Populations
No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment, or mild hepatic impairment (total bilirubin <ULN and AST between 1 to 1.5x ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST ). There are no data on the pharmacokinetics of osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate to severe hepatic impairment (moderate: total bilirubin between 1.5 to 3.0 times ULN and any AST, and severe: total bilirubin between 3.0-10 times ULN and any AST).
Drug Interactions
Effect of Other Drugs on TAGRISSO:
Strong CYP3A Inhibitors: Clinical studies evaluating TAGRISSO in the presence of strong CYP3A inhibitors have not been conducted [see Drug Interactions (7.1)].
Strong CYP3A Inducers: Clinical studies evaluating TAGRISSO in the presence of strong CYP3A inducers have not been conducted [see Drug Interactions (7.1)].
Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.
Effect of Osimertinib on Other Drugs:
CYP450 Metabolic Pathways: Osimertinib is a competitive inhibitor of CYP3A, but not CYP2C8, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 2E1 in vitro. Osimertinib induced CYP3A4 (Pregnane X dependent) and CYP1A2 enzymes.
Transporter Systems: Based on in vitro studies, osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit P-glycoprotein, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2 in vitro.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in in vitro and in vivo assays.
Based on studies in animals, male fertility may be impaired by treatment with TAGRISSO. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5-times the AUC observed in patients at the recommended dose of 80 mg, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males.
Nonclinical female fertility studies have not been conducted. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3-times the AUC observed in patients at the recommended dose of 80 mg. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility.
14 CLINICAL STUDIES
The efficacy of TAGRISSO was demonstrated in two multicenter, single-arm, open-label clinical trials, Study 1 and Study 2, in patients with metastatic EGFR T790M mutation-positive NSCLC who had progressed on prior systemic therapy, including an EGFR TKI. All patients were required to have EGFR T790M mutation-positive NSCLC as detected by the cobas® EGFR mutation test and received TAGRISSO 80 mg once daily. The major efficacy outcome measure of both trials was objective response rate (ORR) according to RECIST v1.1 as evaluated by a Blinded Independent Central Review (BICR). Duration of response (DOR) was an additional outcome measure.
Study 1 population characteristics were: median age 62 years (range 37 to 89), female (66%), White (38%), Asian (58%), never smoker (67%), World Health Organization (WHO) performance status 0 (34%) or 1 (66%), adenocarcinoma histology (97%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (30%), 2 or more prior lines of therapy (70%). Sites of extra-thoracic metastasis included liver (32%), bone (51%), and brain (37%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (71%), L858R (25%), G719X (2%), and S768I (2%).
Study 2 population characteristics were: median age 64 years (range 35 to 88), female (70%), White (34%), Asian (63%), never smoker (76%), World Health Organization (WHO) performance status 0 (40%) or 1 (60%), adenocarcinoma histology (95%), 1 prior line of therapy [EGFR-TKI treatment only, second line, chemotherapy-naïve] (32%), 2 or more prior lines of therapy (68%). Sites of extra-thoracic metastasis included liver (26%), bone (43%), and brain (41%). Somatic EGFR mutations in addition to T790M were exon 19 deletion (65%), L858R (32%), G719X (2%), and S768I (1%).
Efficacy results by BICR from Study 1 and Study 2 are summarized in Table 4. The majority (96%) of patients with confirmed objective responses had ongoing responses ranging from 1.1 to 5.6 months after a median duration of follow-up of 4.2 months for Study 1 and 4.0 months for Study 2.
Table 4 Efficacy Results by BICR in Study 1 and Study 2 

Efficacy Parameter	Study 1 (N=201)	Study 2 (N=210)	Overall2 (N=411)
Objective Response Rate1 (95% CI)	57% (50, 64)	61% (54, 68)	59% (54, 64)
Complete Response	0	1%	0.5%
Partial Response	57%	60%	59%

1 Objective response rate determined by RECIST v1.1 as assessed by BICR
2 Pooled analysis of Study 1 and 2
In a separate dose finding part of Study 1, 63 patients with centrally confirmed T790M positive NSCLC progressed on prior systemic therapy, including an EGFR TKI were administered TAGRISSO 80 mg. In these patients, the BICR-confirmed objective response rate was 51% (32/63) and the median duration of response was 12.4 months from the time of first documented response.
16 HOW SUPPLIED/STORAGE AND HANDLING
80 mg tablets: beige, oval and biconvex tablet marked with “AZ 80” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1350-30).
40 mg tablets: beige, round and biconvex table marked with “AZ 40” on one side and plain on the reverse and are available in bottles of 30 (NDC 0310-1349-30).
Store TAGRISSO bottles at 25°C (77°F). Excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Interstitial Lung Disease/Pneumonitis
Inform patients of the risks of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.1)].
QTc Interval Prolongation
Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. 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 (5.2)].
Cardiomyopathy
• TAGRISSO can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.3)].
Embryo-Fetal Toxicity
• TAGRISSO can cause fetal harm if taken during pregnancy. Advise pregnant women of the potential risk to a fetus.
• Advise females to inform their healthcare provider if they become pregnant or if pregnancy is suspected, while taking TAGRISSO [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].
Females and Males of Reproductive Potential
• Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose [see Use in Specific Populations (8.3)].
• Advise males to use effective contraception during treatment and for 4 months after the final dose of TAGRISSO [see Use in Specific Populations (8.3)].
Lactation
Advise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7

This article Department of pharmacists/medical experts original translation finishing, welcome to reprint! At the same time the procurement of domestic scientific research institutions can contact us: 2363244352.3330889895

TAGRISSO(OSIMERTINIB)在肺癌所致软脑脊膜病患者中显示临床活性
・  ASCO 2016上报告的数据显示，osimertinib可改善EGFRm NSCLC和软脑脊膜病患者的神经系统功能
・  最新结果再次印证了osimertinib能够穿越血脑屏障的临床前证据
英国剑桥 -- (美国商业资讯) -- 阿斯利康(AstraZeneca)今天发布了Tagrisso (osimertinib)在软脑脊膜(LM)病患者中的临床及安全性数据，该病是表皮生长因子受体(EGFR)突变阳性晚期非小细胞肺癌(NSCLC)癌细胞扩散至脑脊液(CSF)所致的并发症。LM是一种与晚期肺癌相关的摧毁性疾病。
美国临床肿瘤学会(ASCO)年会上呈报的BLOOM I期试验更新结果显示，无论患者的T790M状态如何，osimertinib均可导致MRI信号强度变化，提示中枢神经系统(CNS)病灶缩小。
21例采用osimertinib 160毫克每天一次治疗的患者数据显示，7例患者有颅内放射学改善，5例患者有神经系统功能改善，2例患者连续2次访视中CSF未检出肿瘤细胞。21例osimertinib治疗患者中，无人接受合并放疗或鞘内化疗。数据截止时（2016年3月10日），15例患者仍在治疗，其中7例治疗时间超过9个月。
BLOOM研究的进一步数据显示，osimertinib可穿越血脑屏障。9例患者中有6例观察到CSF中EGFR突变水平降幅超过50%，此降低持续至治疗的第9个周期的第1天，其中5例观察到持续降低。上述结果支持既往报道的osimertinib穿越血脑屏障的临床前数据。
台北国立台湾大学医院、国立台湾大学癌症研究中心的杨志新(James CH Yang)博士说：“软脑脊膜病的预后极差，因此，osimertinib中观察到的安全性、耐受性和活性令人鼓舞。BLOOM研究中，我们发现软脑脊膜病患者的中枢神经系统病灶有缩小，同时伴有神经系统改善。该结果印证了osimertinib在临床前及临床研究中的既往结果，证明了osimertinib在伴有中枢神经系统转移的难治性患者中的前景。”
在软脑脊膜病中，癌细胞扩散至包裹脑和脊索的膜上。该病目前采用全身或鞘内化疗、全脑放疗或EGFR酪氨酸激酶抑制剂(TKI)，中位总生存期4.5-11个月。3,4 但多数现有EGFR-TKI穿越血脑屏障的能力有限，无法有效治疗或预防脑转移。
osimertinib 160毫克在最长达11个月的治疗期间耐受性可处治。患者最常报告的不良事件有腹泻（58%总体；5% ≥3级）、恶心（48%总体；0% ≥3级）和皮疹（43%总体；0% ≥3级）。间质性肺病、高血糖或QT延长病例未见报告。
osimertinib最近在美国、欧盟、日本和以色列获得加快核准，首个适应证是治疗EGFR T790M突变阳性局部进展/转移性NSCLC患者。韩国也已核准osimertinib用于同一适应证。
阿斯利康致力于探索osimertinib在肺癌中的全部潜力，包括辅助治疗和局部进展/转移性EGFRm一线治疗、有或无脑转移的患者以及伴软脑脊膜病的患者。
关于非小细胞肺癌(NSCLC)
肺癌是男女癌症的主要死因，约占所有癌症死因的三分之一，高于乳腺癌、前列腺癌和结直肠癌之和。EGFRm型NSCLC患者占欧洲NSCLC患者的10-15%，10占亚洲NSCLC患者的30-40%，对现有的EGFR-TKIs类药物特别敏感，此类药物可阻断促进肿瘤细胞生长的细胞信号传递通路。不过，肿瘤几乎都会发生耐药，导致疾病进展。13在接受吉非替尼和厄洛替尼等已获准的EGFR-TKIs治疗的患者中，约三分之二发生的耐药由T790M继发突变所致。
关于软脑脊膜病
在软脑脊膜病中，癌细胞扩散至包裹脑和脊索的膜上。它是一种并发症，累及3-5%的NSCLC患者，以及9%的EGFRm NSCLC患者。治疗具有挑战性，因为多数EGFR-TKI治疗药物难以穿越血脑屏障，使药物难以达到脑和脊索。EGFRm NSCLC和软脑脊膜病患者的平均生存期介于4.5至11个月。最近报道的“真实世界”回顾性分析中，EGFRm NSCLC患者采用EGFR-TKIs治疗，总生存期约为30个月。
关于osimertinib
osimertinib 80毫克每天一次片剂是首个适用于局部进展或转移性EGFR T790M突变阳性NSCLC成人患者的药物。非临床体外研究显示，在有临床意义的EGFR和T790M突变型NSCLC细胞株中，osimertinib具有抗击突变型EGFR磷酸化的高效价和抑制活性，而其抗击野生型细胞株EGFR的活性显著较小。
证实性III期AURA3研究在EGFR T790M突变阳性、局部进展或EGFR-TKI治疗后进展的转移性NSCLC患者中比较osimertinib与含铂两药化疗方案。该药也在研究用于辅助和转移性一线治疗，包括有和无脑转移的患者、软脑脊膜病、以及联合治疗。