新一代肺癌靶向药TAGRISSO(osimertinib/AZD9291)获批美国FDA加速批准上市 2015年11月13日，口服新药Tagrisso（Osimertinib）获美国食品药品监督管理局（以下简称FDA）加速批准，用于治疗携带特定表皮生长因子受体（EGFR）突变（T790M）、在接受其他EGFR抑制剂后疾病进展的晚期非小细胞肺癌（NSCLC）患者。 据美国国家癌症研究所报道，肺癌是美国癌症死亡的主要原因，2015年美国预计有221,200名新增肺癌病例和158,040名肺癌死亡病例。NSCLC是最常见的肺癌，当癌细胞形成于肺组织时就会出现NSCLC，而EGFR基因与癌细胞的生长与扩散有关。 “我们对肺癌的分子基础以及肺癌为何对既往治疗产生耐药的认识在不断加深，”FDA药品评价与研究中心的血液与肿瘤药品办公室主任Richard Pazdur博士说。“大量临床试验证据表明，Tagrisso疗效显著，使半数以上服用该药患者的肿瘤大幅度缩小，该药的获批为获得性耐药EGFR T790M突变阳性NSCLC患者提供了一种新治疗选择。” 与Tagrisso同时获批的还有用于检测获得性耐药EGFR T790M突变的首款诊断性检测（cobas EGFR突变检测v2）。 “批准安全有效的药物和伴随诊断检测将继续成为肿瘤学领域的重大进展，”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。“cobas EGFR突变检测v2的获批满足了检测EGFR T790M突变的需求，而这可以使疗效发生改变。” 两项多中心、单臂临床试验证实了Tagrisso的安全性与有效性。这两项临床试验共入组411名在接受某种EGFR抑制剂后疾病进展的EGFR T790M突变阳性晚期NSCLC患者。经过Tagrisso治疗，第一项临床试验有57%的患者、第二项临床试验有61%的患者都达到了肿瘤完全消失或部分缩小（即客观有效率）。 Tagrisso的最常见副作用有腹泻以及皮肤和指甲疾病如皮肤干燥、皮疹、指甲周围感染或发红。此外，Tagrisso可能会导致肺部炎症和心脏损伤等严重的副作用，同时也可能会对发育中的胎儿造成伤害。 FDA授予Tagrisso突破性疗法认定、优先审批资格和孤儿药认定，是因为申办方通过初步临床证据证实，相比现有治疗，该药物能实质性地改善患者病情；申请提交时，该药物有可能显著提高严重疾病治疗的安全性或有效性；该药物旨在用于治疗罕见病。 FDA经加速审批程序批准了Tagrisso。加速审批程序用于批准重大或威胁生命疾病的治疗药物。如果新药物的临床数据显示，该药物能够影响替代终点指标（可合理预测患者受益的指标），那么这种药物就有资格获得加速审批。该审批程序让患者能够在药企进行证实性临床试验期间就提早一步获得有望上市的新药治疗。 Tagrisso由位于美国特拉华州威尔明顿的阿斯利康制药公司推广上市。cobas EGFR突变检测v2由位于美国加州普莱森顿的罗氏分子诊断公司推广上市。 包装规格[本品美国上市包装] TAGRISSO 40MG TAB 30/EA  OSIMERTINIB  ASTRA ZENECA  00310-1349-30 TAGRISSO 80MG TAB 30/EA  OSIMERTINIB  ASTRA ZENECA  00310-1350-30  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 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)]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5e81b4a7-b971-45e1-9c31-29cea8c87ce7