US-41778

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) tablets, for oral useInitial U.S. Approval: 2015

--------------------------------- RECENT MAJOR CHANGES --------------------------------Dosage and Administration (2.4) 12/2019Warnings and Precautions (5.5) 12/2019

--------------------------------- INDICATIONS AND USAGE ---------------------------------TAGRISSO is a kinase inhibitor indicated for

• thefirst-linetreatmentofpatientswithmetastaticNSCLCwhosetumorshaveepidermalgrowthfactorreceptor(EGFR)exon19deletionsorexon21L858Rmutations,asdetectedbyanFDA-approvedtest.(1.1,2.1)

• the treatment of patients with metastatic EGFR T790M mutation-positiveNSCLC,asdetectedbyanFDA-approvedtest,whosediseasehasprogressedonorafterEGFRTKItherapy.(1.2,2.1)

----------------------------- DOSAGE AND ADMINISTRATION ------------------------------Recommendeddosage:80mgorallyoncedaily,withorwithoutfood.(2.2)

--------------------------- DOSAGE FORMS AND STRENGTHS -----------------------------Tablets:80mgand40mg.(3)

----------------------------------- CONTRAINDICATIONS ------------------------------------None.(4)

----------------------------- WARNINGS AND PRECAUTIONS ------------------------------• Interstitial Lung Disease (ILD)/Pneumonitis: Occurred in 3.9% of patients.

PermanentlydiscontinueTAGRISSOinpatientsdiagnosedwithILD/Pneumonitis.(5.1)

• QTc Interval Prolongation: Monitor electrocardiograms and electrolytes inpatientswhohaveahistoryorpredispositionforQTcprolongation,orthosewhoaretakingmedicationsthatareknowntoprolongtheQTcinterval.WithholdthenrestartatareduceddoseorpermanentlydiscontinueTAGRISSO. (2.4, 5.2)

• Cardiomyopathy: Occurred in 2.6% of patients. Conduct cardiac monitoring,including left ventricular ejection fraction (LVEF) assessment in patients withcardiac risk factors. (2.4, 5.3)

• Keratitis: Promptly refer patients with signs and symptoms of keratitis to anophthalmologistforevaluation. (5.4)

• Erythema Multiforme and Stevens-Johnson Syndrome: Withhold TAGRISSOif erythema multiforme major (EMM) or Stevens-Johnson syndrome (SJS) issuspectedandpermanentlydiscontinueifconfirmed.(2.4,5.5)

• Embryo-Fetal Toxicity: TAGRISSO can cause fetal harm. Advise females ofpotential risk to the fetus and to use effective contraception during treatmentwithTAGRISSOandfor6weeksafterfinaldose.Advisemalestouseeffectivecontraceptionfor4months,afterthelastdoseofTAGRISSO. (5.6, 8.1, 8.3)

----------------------------------- ADVERSE REACTIONS ------------------------------------Mostcommonadversereactions(≥20%)werediarrhea,rash,dryskin,nailtoxicity,stomatitis,fatigueanddecreasedappetite.(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 ------------------------------------StrongCYP3A Inducers:Avoid if possible. If notpossible, increaseTAGRISSO to 160mgdailyinpatientsreceivingastrongCYP3A4inducer.(2.4,7.1)

----------------------------- USE IN SPECIFIC POPULATIONS ------------------------------Lactation:Donotbreastfeed.(8.2)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 06/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE 1.1 First-lineTreatmentofEGFRMutation-PositiveMetastatic Non-SmallCellLungCancer(NSCLC) 1.2 PreviouslyTreatedEGFRT790MMutation-PositiveMetastaticNSCLC2 DOSAGE AND ADMINISTRATION 2.1 PatientSelection 2.2 Recommended Dosage Regimen 2.3 AdministrationtoPatientsWhoHaveDifficultySwallowingSolids 2.4 DosageModifications3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 InterstitialLungDisease/Pneumonitis 5.2 QTcIntervalProlongation 5.3 Cardiomyopathy 5.4 Keratitis 5.5 ErythemaMultiformeandStevens-JohnsonSyndrome 5.6 Embryo-FetalToxicity6 ADVERSE REACTIONS 6.1 ClinicalTrialsExperience 6.2 PostmarketingExperience7 DRUG INTERACTIONS 7.1 EffectofOtherDrugsonOsimertinib 7.2 EffectofOsimertinibonOtherDrugs 7.3 DrugsThatProlongtheQTcInterval

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 FemalesandMalesofReproductivePotential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 RenalImpairment 8.7 HepaticImpairment11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1MechanismofAction 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1Carcinogenesis,Mutagenesis,ImpairmentofFertility14 CLINICAL STUDIES 14.1PreviouslyUntreatedEGFRMutation-PositiveMetastatic Non-SmallCellLungCancer 14.2PreviouslyTreatedEGFRT790MMutation-PositiveMetastatic Non-SmallCellLungCancer16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION

*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.

TAGRISSO® (osimertinib) tablets, for oral use 2

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)TAGRISSO is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factorreceptor(EGFR)exon19deletionsorexon21L858Rmutations,asdetectedbyanFDA-approvedtest [see Dosage and Administration (2.1)].

1.2 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLCTAGRISSO is indicated for the treatmentofpatientswithmetastaticEGFRT790Mmutation-positiveNSCLC,asdetectedbyanFDA-approvedtest,whosediseasehasprogressedonorafterEGFRtyrosinekinaseinhibitor(TKI)therapy[see Dosage and Administration (2.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient SelectionSelectpatients for thefirst-line treatmentofmetastaticEGFR-positiveNSCLCwithTAGRISSO based on the presence of EGFR exon 19 deletions or exon 21 L858Rmutationsintumororplasmaspecimens[see Clinical Studies (14)]. If these mutations arenotdetectedinaplasmaspecimen,testtumortissueiffeasible.SelectpatientsforthetreatmentofmetastaticEGFRT790Mmutation-positiveNSCLCwithTAGRISSO followingprogressiononor after EGFRTKI therapybasedon thepresenceofanEGFRT790Mmutation in tumororplasmaspecimens[see Clinical Studies (14)].TestingforthepresenceoftheT790Mmutationinplasmaspecimensisrecommendedonlyinpatientsforwhomatumorbiopsycannotbeobtained.Ifthismutationisnotdetectedinaplasmaspecimen,re-evaluatethefeasibilityofbiopsyfor tumor tissue testing.InformationonFDA-approvedtestsforthedetectionofEGFRmutationsisavailableathttp://www.fda.gov/companiondiagnostics.

2.2 Recommended Dosage RegimenTherecommendeddosageofTAGRISSO is80mg tabletonceadayuntildiseaseprogressionorunacceptabletoxicity.TAGRISSOcanbetakenwithorwithoutfood.IfadoseofTAGRISSOismissed,donotmakeupthemisseddoseandtakethenextdoseasscheduled.

2.3 Administration to Patients Who Have Difficulty Swallowing SolidsDispersetabletin60mL(2ounces)ofnon-carbonatedwateronly.Stiruntiltabletisdispersedintosmallpieces(thetabletwillnotcompletelydissolve)andswallowimmediately. Do not crush, heat, or ultrasonicate during preparation. Rinse thecontainerwith120mLto240mL(4to8ounces)ofwaterandimmediatelydrink.If administration via nasogastric tube is required, disperse the tablet as above in 15mLofnon-carbonatedwater,andthenuseanadditional15mLofwatertotransferanyresiduestothesyringe.Theresulting30mLliquidshouldbeadministeredasperthenasogastrictubeinstructionswithappropriatewaterflushes(approximately30mL).

2.4 Dosage ModificationsAdverseReactions

Table 1. Recommended Dosage Modifications for TAGRISSO

Target Organ Adverse Reaction* Dosage Modification

Pulmonary [see Warnings and Precautions (5.1)]

Interstitiallungdisease(ILD)/Pneumonitis

PermanentlydiscontinueTAGRISSO.

Cardiac [seeWarnings andPrecautions (5.2, 5.3)]

QTc† intervalgreaterthan 500mseconatleast 2separateECGs‡

WithholdTAGRISSOuntilQTcintervalislessthan481msecorrecoverytobaselineifbaselineQTcisgreaterthanorequalto481 msec, then resume at 40 mg dose.

QTcintervalprolongation withsigns/symptomsof life-threateningarrhythmia

PermanentlydiscontinueTAGRISSO.

Symptomaticcongestive heartfailure

PermanentlydiscontinueTAGRISSO.

Target Organ Adverse Reaction* Dosage Modification

Cutaneous [seeWarnings andPrecautions (5.5)]

Stevens-Johnsonsyndrome(SJS),ErythemaMultiformeMajor(EMM)

WithholdTAGRISSOifsuspectedandpermanentlydiscontinueifconfirmed.

Other [see AdverseReactions (6.1)]

AdversereactionofGrade3orgreaterseverity

WithholdTAGRISSOforupto3weeks.

IfimprovementtoGrade0-2within3weeks

Resume at 80 mg or 40 mg daily.

Ifnoimprovementwithin 3weeks

PermanentlydiscontinueTAGRISSO.

*Adverse reactionsgradedby theNationalCancer InstituteCommonTerminologyCriteria for AdverseEventsversion4.0(NCICTCAEv4.0).

† QTc=QTintervalcorrectedforheartrate‡ ECGs=Electrocardiogram

Drug Interactions

Strong CYP3A4 InducersIfconcurrentuseisunavoidable,increaseTAGRISSOdosageto160mgdailywhenco-administeringwithastrongCYP3Ainducer.ResumeTAGRISSOat80mg3weeksafterdiscontinuationofthestrongCYP3A4inducer[see Drug Interactions (7) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS80mgtablets:beige,ovalandbiconvextabletmarkedwith“AZ80”ononesideandplainonthereverse.40mgtablets:beige,roundandbiconvextabletmarkedwith“AZ40”ononesideandplainonthereverse.

4 CONTRAINDICATIONSNone.

5 WARNINGS AND PRECAUTIONS

5.1 Interstitial Lung Disease/PneumonitisInterstitiallungdisease(ILD)/pneumonitisoccurredin3.9%ofthe1142TAGRISSO-treatedpatients;0.4%ofcaseswerefatal.WithholdTAGRISSOandpromptlyinvestigateforILDinpatientswhopresentwithworseningofrespiratorysymptomswhichmaybeindicativeofILD(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 ProlongationHeartrate-correctedQT(QTc)intervalprolongationoccursinpatientstreatedwithTAGRISSO.Ofthe1142patientstreatedwithTAGRISSOinclinicaltrials,0.9%werefoundtohaveaQTc>500msec,and3.6%ofpatientshadanincreasefrombaselineQTc > 60 msec [see Clinical Pharmacology (12.2)]. No QTc-related arrhythmias werereported.ClinicaltrialsofTAGRISSOdidnotenrollpatientswithbaselineQTcof>470msec.ConductperiodicmonitoringwithECGsandelectrolytesinpatientswithcongenitallong QTc syndrome, congestive heart failure, electrolyte abnormalities, or thosewho are taking medications known to prolong the QTc interval. Permanentlydiscontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptomsoflife-threateningarrhythmia[see Dosage and Administration (2.4)].

5.3 CardiomyopathyAcross clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiacfailure, congestiveheart failure, pulmonary edemaordecreasedejection fraction)occurredin2.6%ofthe1142TAGRISSO-treatedpatients;0.1%ofcardiomyopathycaseswerefatal.Adeclineinleftventricularejectionfraction(LVEF)≥10%frombaselineandtolessthan50%LVEFoccurredin3.9%of908patientswhohadbaselineandatleastonefollow-upLVEFassessment.Conduct cardiac monitoring, including assessment of LVEF at baseline and duringtreatment,inpatientswithcardiacriskfactors.AssessLVEFinpatientswhodevelop relevant cardiac signs or symptoms during treatment. For symptomaticcongestive heart failure, permanently discontinue TAGRISSO [see Dosage and Administration (2.4)].

Table 1. Recommended Dosage Modifications for TAGRISSO (cont’d)

TAGRISSO® (osimertinib) tablets, for oral use 3

5.4 Keratitis

Keratitiswasreported in0.7%of1142patients treatedwithTAGRISSO inclinicaltrials.Promptlyreferpatientswithsignsandsymptomssuggestiveofkeratitis(suchas eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or redeye)toanophthalmologist.

5.5 Erythema Multiforme and Stevens-Johnson SyndromePostmarketing cases consistent with Stevens-Johnson syndrome (SJS) anderythema multiforme major (EMM) have been reported in patients receivingTAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanentlydiscontinueifconfirmed.

5.6 Embryo-Fetal ToxicityBased on data from animal studies and its mechanism of action, TAGRISSO cancausefetalharmwhenadministeredtoapregnantwoman.Inanimalreproductionstudies,osimertinibcausedpost-implantationfetal losswhenadministeredduringearlydevelopmentatadoseexposure1.5timestheexposureattherecommendedclinical dose. When males were treated prior to mating with untreated females,there was an increase in preimplantation embryonic loss at plasma exposures ofapproximately0.5timesthoseobservedattherecommendeddoseof80mgoncedaily.VerifypregnancystatusoffemalesofreproductivepotentialpriortoinitiatingTAGRISSO.Advisepregnantwomenofthepotentialrisktoafetus.Advisefemalesof reproductive potential to use effective contraception during treatment withTAGRISSOandfor6weeksafterthefinaldose.Advisemaleswithfemalepartnersofreproductivepotentialtouseeffectivecontraceptionfor4monthsafterthefinaldose[see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONSThefollowingadversereactionsarediscussedingreaterdetailinothersectionsofthelabeling:InterstitialLungDisease/Pneumonitis[see Warnings and Precautions (5.1)]QTcIntervalProlongation[see Warnings and Precautions (5.2)]Cardiomyopathy[see Warnings and Precautions (5.3)]Keratitis[see Warnings and Precautions (5.4)] ErythemamultiformeandStevens-Johnsonsyndrome[see Warnings and Precautions (5.5)]

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adversereactionratesobservedintheclinicaltrialsofadrugcannotbedirectlycomparedtoratesintheclinicaltrialsofanotherdrugandmaynotreflecttheratesobservedinpractice.The data in the Warnings and Precautions section reflect exposure to TAGRISSOin 1142 patients with EGFR mutation-positive NSCLC who received TAGRISSO atthe recommendeddoseof80mgoncedaily in tworandomized,active-controlledtrials[FLAURA(n=279)andAURA3(n=279)],twosinglearmtrials[AURAExtension(n=201) and AURA2 (n=210)], and one dose-finding study, AURA1 (n=173) [see Warnings and Precautions (5)].ThedatadescribedbelowreflectexposuretoTAGRISSO(80mgdaily)in558patientswithEGFRmutation-positive,metastaticNSCLCintworandomized,active-controlledtrials[FLAURA(n=279)andAURA3(n=279)].Patientswithahistoryofinterstitiallungdisease,druginducedinterstitialdiseaseorradiationpneumonitisthatrequiredsteroidtreatment,seriousarrhythmiaorbaselineQTcintervalgreaterthan470mseconelectrocardiogramwereexcludedfromenrollmentinthesestudies.

PreviouslyUntreatedEGFRMutation-PositiveMetastaticNon-SmallCellLungCancerThe safety of TAGRISSO was evaluated in FLAURA, a multicenter internationaldouble-blind randomized (1:1) active controlled trial conducted in 556 patientswithEGFRexon19deletionorexon21L858Rmutation-positive,unresectableormetastaticNSCLCwhohadnotreceivedprevioussystemictreatmentforadvanceddisease.ThemediandurationofexposuretoTAGRISSOwas16.2months.The most common adverse reactions (≥20%) in patients treated with TAGRISSOwere diarrhea (58%), rash (58%), dry skin (36%), nail toxicity (35%), stomatitis(29%),anddecreasedappetite(20%).Seriousadversereactionswerereportedin4%ofpatientstreatedwithTAGRISSO;themostcommonseriousadversereactions(≥1%)werepneumonia(2.9%),ILD/pneumonitis(2.1%),andpulmonaryembolism(1.8%).Dosereductionsoccurredin2.9%ofpatientstreatedwithTAGRISSO.Themost frequentadverse reactions leading todose reductionsor interruptionswere

prolongationof theQT intervalasassessedbyECG(4.3%),diarrhea(2.5%),andlymphopenia (1.1%). Adverse reactions leading to permanent discontinuationoccurred in 13% of patients treated with TAGRISSO. The most frequent adversereactionleadingtodiscontinuationofTAGRISSOwasILD/pneumonitis(3.9%).Tables2and3summarizecommonadversereactionsandlaboratoryabnormalitieswhichoccurredinFLAURA.FLAURAwasnotdesignedtodemonstrateastatisticallysignificantreductioninadversereactionratesforTAGRISSO,orforthecontrolarm,foranyadversereactionlistedinTables2and3.Table 2. Adverse Reactions Occurring in ≥10% of Patients Receiving

TAGRISSO in FLAURA*

Adverse Reaction TAGRISSO

(N=279)

EGFR TKI comparator

(gefitinib or erlotinib)

(N=277)

Any Grade (%)

Grade 3 or higher (%)

Any Grade (%)

Grade 3 or higher (%)

Gastrointestinal Disorders

Diarrhea† 58 2.2 57 2.5

Stomatitis 29 0.7 20 0.4

Nausea 14 0 19 0

Constipation 15 0 13 0

Vomiting 11 0 11 1.4

Skin Disorders

Rash‡ 58 1.1 78 6.9

Dry skin§ 36 0.4 36 1.1

Nailtoxicity¶ 35 0.4 33 0.7

Pruritus# 17 0.4 17 0

Metabolism and Nutrition Disorders

Decreasedappetite 20 2.5 19 1.8

Respiratory, Thoracic and Mediastinal Disorders

Cough 17 0 15 0.4

Dyspnea 13 0.4 7 1.4

Neurologic Disorders

Headache 12 0.4 7 0

Cardiac Disorders

ProlongedQTIntervalþ

10 2.2 4 0.7

General Disorders and Administration Site Conditions

Fatigueb 21 1.4 15 1.4

Pyrexia 10 0 4 0.4

Infection and Infestation Disorders

UpperRespiratoryTract Infection

10 0 7 0

*NCICTCAEv4.0†Onegrade5(fatal)eventwasreported(diarrhea)forEGFRTKIcomparator‡ Includesrash,rashgeneralized,rasherythematous,rashmacular,rashmaculo-papular,rash

papular,rashpustular,rashpruritic,rashvesicular,rashfollicular,erythema,folliculitis,acne,dermatitis,dermatitisacneiform,drugeruption,skinerosion.

§Includesdryskin,skinfissures,xerosis,eczema,xeroderma.¶Includes nail bed disorder, nail bed inflammation, nail bed infection, nail discoloration, nail

pigmentation,naildisorder,nailtoxicity,naildystrophy,nailinfection,nailridging,onychalgia,onychoclasis,onycholysis,onychomadesis,onychomalacia,paronychia.

#Includespruritus,pruritusgeneralized,eyelidpruritus.þThefrequencyof“ProlongedQTInterval”representsreportedadverseeventsintheFLAURA

study.FrequenciesofQTcintervalsof>500msor>60msarepresentedinSection5.2.bIncludesfatigue,asthenia.

TAGRISSO® (osimertinib) tablets, for oral use 4

Table 3. Laboratory Abnormalities Worsening from Baseline in ≥ 20% of Patients in FLAURA

Laboratory Abnormality*, †

TAGRISSO

(N=279)

EGFR TKI comparator

(gefitinib or erlotinib)

(N=277)

Change from Baseline

All Grades (%)

Change from Baseline to Grade 3 or

Grade 4 (%)

Change from Baseline

All Grades (%)

Change from Baseline to Grade 3 or

Grade 4(%)

Hematology

Lymphopenia 63 5.6 36 4.2

Anemia 59 0.7 47 0.4

Thrombocytopenia 51 0.7 12 0.4

Neutropenia 41 3.0 10 0

Chemistry

Hyperglycemia‡ 37 0 31 0.5

Hypermagnesemia 30 0.7 11 0.4

Hyponatremia 26 1.1 27 1.5

Increased AST 22 1.1 43 4.1

IncreasedALT 21 0.7 52 8

Hypokalemia 16 0.4 22 1.1

Hyperbilirubinemia 14 0 29 1.1

*NCICTCAEv4.0†Eachtestincidence,exceptforhyperglycemia,isbasedonthenumberofpatientswhohadboth

baselineandatleastoneon-studylaboratorymeasurementavailable(TAGRISSOrange:267-273andEGFRTKIcomparatorrange:256-268)

‡Hyperglycemia is based on the number of patients who had both baseline and at least one on-studylaboratorymeasurementavailable:TAGRISSO(179)andEGFRcomparator(191)

Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell LungCancerThesafetyofTAGRISSOwasevaluatedinAURA3,amulticenterinternationalopenlabelrandomized(2:1)controlledtrialconductedin419patientswithunresectableormetastaticEGFRT790Mmutation-positiveNSCLCwhohadprogressivediseasefollowingfirstlineEGFRTKItreatment.Atotalof279patientsreceivedTAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, orinvestigatordeterminationthatthepatientwasnolongerbenefitingfromtreatment.A total of 136 patients received pemetrexed plus either carboplatin or cisplatin every three weeks for up to 6 cycles; patients without disease progression after4 cycles of chemotherapy could continue maintenance pemetrexed until diseaseprogression,unacceptabletoxicity,orinvestigatordeterminationthatthepatientwasno longerbenefiting fromtreatment.LeftVentricularEjectionFraction(LVEF)wasevaluatedatscreeningandevery12weeks.Themediandurationoftreatmentwas8.1monthsforpatientstreatedwithTAGRISSOand4.2monthsforchemotherapy-treated patients. The trial population characteristics were: median age 62 years, age less than 65 (58%), female (64%), Asian (65%), never smokers (68%), andECOGPS0or1(100%).

The most common adverse reactions (≥20%) in patients treated with TAGRISSOwerediarrhea(41%),rash(34%),dryskin(23%),nailtoxicity(22%),andfatigue(22%). Serious adverse reactions were reported in 18% of patients treated withTAGRISSOand26%inthechemotherapygroup.Nosingleseriousadversereactionwasreported in2%ormorepatients treatedwithTAGRISSO.Onepatient (0.4%)treatedwithTAGRISSOexperiencedafataladversereaction(ILD/pneumonitis).Dose reductions occurred in 2.9% of patients treated with TAGRISSO. The mostfrequent adverse reactions leading to dose reductions or interruptions wereprolongation of the QT interval as assessed by ECG (1.8%), neutropenia (1.1%),anddiarrhea (1.1%).Adverse reactions resulting inpermanentdiscontinuationofTAGRISSOoccurred in7%ofpatients treatedwithTAGRISSO.Themost frequentadversereactionleadingtodiscontinuationofTAGRISSOwasILD/pneumonitis(3%).Tables4and5summarizecommonadversereactionsandlaboratoryabnormalitieswhichoccurredinTAGRISSO-treatedpatientsinAURA3.AURA3wasnotdesignedto demonstrate a statistically significant reduction in adverse reaction rates forTAGRISSO,orforthecontrolarm,foranyadversereactionlistedinTables4and5.

Table 4. Adverse Reactions Occurring in ≥10% of Patients Receiving TAGRISSO in AURA3*

Adverse ReactionTAGRISSO(N=279)

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)

(N=136)

All Grades†(%)

Grade 3/4†(%)

All Grades†(%)

Grade 3/4†(%)

Gastrointestinal Disorders

Diarrhea 41 1.1 11 1.5

Nausea 16 0.7 49 3.7

Stomatitis 15 0 15 1.5

Constipation 14 0 35 0

Vomiting 11 0.4 20 2.2

Skin Disorders

Rash‡ 34 0.7 5.9 0

Dry skin§ 23 0 4.4 0

Nailtoxicity¶ 22 0 1.5 0

Pruritus# 13 0 5.1 0

Metabolism and Nutrition Disorders

Decreasedappetite 18 1.1 36 2.9

Respiratory, Thoracic and Mediastinal Disorders

Cough 17 0 14 0

Musculoskeletal and Connective Tissue Disorders

Backpain 10 0.4 9 0.7

General Disorders and Administration Site Conditions

Fatigueþ 22 1.8 40 5.1

*NCICTCAEv4.0.† Nograde4eventswerereported.‡Includesrash,rashgeneralized,rasherythematous,rashmacular,rashmaculo-papular,rash

papular,rashpustular,erythema,folliculitis,acne,dermatitisandacneiformdermatitis.§ Includesdryskin,eczema,skinfissures,xerosis.¶Includes nail disorders, nail bed disorders, nail bed inflammation, nail bed tenderness, nail

discoloration,naildisorder,naildystrophy,nailinfection,nailridging,nailtoxicity,onychoclasis,onycholysis,onychomadesis,paronychia.

# Includespruritus,pruritusgeneralized,eyelidpruritus.þIncludesfatigue,asthenia.

TAGRISSO® (osimertinib) tablets, for oral use 5

Table 5. Laboratory Abnormalities Worsening from Baseline in ≥20% of Patients in AURA3

Laboratory Abnormality*, †

TAGRISSO

(N=279)

Chemotherapy (Pemetrexed/Cisplatin or Pemetrexed/Carboplatin)

(N=131)

Change from Baseline

All Grades (%)

Change from Baseline to Grade 3 or

Grade 4 (%)

Change from Baseline

All Grades(%)

Change from Baseline to Grade 3 or

Grade 4(%)

Hematology

Anemia 43 0 79 3.1

Lymphopenia 63 8.2 61 9.9

Thrombocytopenia 46 0.7 48 7.4

Neutropenia 27 2.2 49 12

Chemistry

Hypermagnesemia† 27 1.8 9.2 1.5

Hyponatremia† 26 2.2 36 1.5

Hyperglycemia‡ 20 0 NA NA

Hypokalemia† 9.0 1.4 18 1.5

NA=notapplicable* NCICTCAEv4.0†Eachtest incidence,except forhyperglycemia, isbasedonthenumberofpatientswhohad

both baseline and at least one on-study laboratory measurement available (TAGRISSO 279,Chemotherapycomparator131)

‡Hyperglycemia isbasedon thenumberofpatientswhohadbothbaselineandat leastone on-studylaboratorymeasurementavailable(TAGRISSO270,Chemotherapy5;fastingglucosewasnotaprotocolrequirementforpatientsinthechemotherapyarm)

6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use ofTAGRISSO. Because these reactions are reported voluntarily from a populationof uncertain size, it is not always possible to reliably estimate their frequency orestablishacausalrelationshiptodrugexposure.Cutaneous:Stevens-Johnsonsyndrome,erythemamultiforme

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on Osimertinib

StrongCYP3AInducersCo-administeringTAGRISSOwithastrongCYP3A4inducerdecreasedtheexposure of osimertinib compared to administering TAGRISSO alone [see Clinical Pharmacology (12.3)].Decreasedosimertinibexposuremayleadtoreducedefficacy.Avoid co-administering TAGRISSO with strong CYP3A inducers. Increase theTAGRISSOdosagewhenco-administeringwithastrongCYP3A4inducerifconcurrentuseisunavoidable[see Dosage and Administration (2.4)].NodoseadjustmentsarerequiredwhenTAGRISSOisusedwithmoderateand/orweakCYP3Ainducers.7.2 Effect of Osimertinib on Other DrugsCo-administering TAGRISSO with a breast cancer resistant protein (BCRP) orP-glycoprotein(P-gp)substrateincreasedtheexposureofthesubstratecomparedtoadministeringitalone[see Clinical Pharmacology (12.3)].IncreasedBCRPorP-gpsubstrateexposuremayincreasetheriskofexposure-relatedtoxicity.Monitor for adverse reactions of the BCRP or P-gp substrate, unless otherwiseinstructedinitsapprovedlabeling,whenco-administeredwithTAGRISSO.

7.3 Drugs That Prolong the QTc IntervalTheeffectofco-administeringmedicinalproductsknowntoprolongtheQTcintervalwith TAGRISSO is unknown. When feasible, avoid concomitant administration ofdrugsknowntoprolongtheQTcintervalwithknownriskofTorsadesdepointes.Ifnotfeasibletoavoidconcomitantadministrationofsuchdrugs,conductperiodicECGmonitoring [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk SummaryBased on data from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TAGRISSO can cause fetal harm when administered to apregnantwoman.TherearenoavailabledataonTAGRISSOuseinpregnantwomen.Administrationofosimertinibtopregnantratswasassociatedwithembryolethalityand reduced fetal growth at plasma exposures 1.5 times the exposure at therecommendedclinicaldose(see Data).Advisepregnantwomenofthepotentialriskto a fetus.IntheU.S.generalpopulation,theestimatedbackgroundriskofmajorbirthdefectsandmiscarriageinclinically-recognizedpregnanciesis2%to4%and15%to20%,respectively.

Data

AnimalDataWhenadministeredtopregnantratspriortoembryonicimplantationthroughtheendoforganogenesis(gestationdays2-20)atadoseof20mg/kg/day,whichproducedplasma exposures of approximately 1.5 times the clinical exposure, osimertinibcaused post-implantation loss and early embryonic death. When administered topregnant rats from implantation through theclosureof thehardpalate (gestationdays6to16)atdosesof1mg/kg/dayandabove(0.1timestheAUCobservedattherecommendedclinicaldoseof80mgoncedaily),anequivocal increaseintherate of fetal malformations and variations was observed in treated litters relativetothoseofconcurrentcontrols.Whenadministeredtopregnantdamsatdosesof30 mg/kg/day during organogenesis through lactation Day 6, osimertinib causedan increase in total litter loss and postnatal death. At a dose of 20 mg/kg/day,osimertinibadministrationduring thesameperiod resulted in increasedpostnataldeath aswell as a slight reduction inmeanpupweight at birth that increased inmagnitudebetweenlactationdays4and6.

8.2 LactationRisk SummaryTherearenodataonthepresenceofosimertiniboritsactivemetabolitesinhumanmilk, the effects of osimertinib on the breastfed infant or on milk production.Administration to rats during gestation and early lactation was associated withadverse effects, including reduced growth rates and neonatal death [see Use in Specific Populations (8.1)].Becauseofthepotentialforseriousadversereactionsinbreastfedinfantsfromosimertinib,advisewomennottobreastfeedduringtreatmentwithTAGRISSOandfor2weeksafterthefinaldose.

8.3 Females and Males of Reproductive Potential

Pregnancy TestingVerify thepregnancystatusof femalesof reproductivepotential prior to initiatingTAGRISSO.

ContraceptionTAGRISSOcancausefetalharmwhenadministeredtopregnantwomen[see Use in Specific Populations (8.1)].

FemalesAdvise females of reproductive potential to use effective contraception duringtreatmentwithTAGRISSOandfor6weeksafterthefinaldose[see Use in Specific Populations (8.1)].

MalesAdvisemalepatientswithfemalepartnersofreproductivepotentialtouseeffectivecontraceptionduringandfor4monthsfollowingthefinaldoseofTAGRISSO[see Nonclinical Toxicology (13.1)].

InfertilityBased on animal studies, TAGRISSO may impair fertility in females and malesof reproductive potential. The effects on female fertility showed a trend towardreversibility.Itisnotknownwhethertheeffectsonmalefertilityarereversible[see Nonclinical Toxicology (13.1)].

8.4 Pediatric UseThe safety and effectiveness of TAGRISSO in pediatric patients have not beenestablished.

8.5 Geriatric UseForty-threepercent(43%)ofthe1142patientsinFLAURA(n=279),AURA3(n=279),AURAExtension(n=201),AURA2(n=210),andAURA1,(n=173)were65yearsofageandolder.Nooveralldifferencesineffectivenesswereobservedbasedonage.ExploratoryanalysissuggestsahigherincidenceofGrade3and4adversereactions(13.4%versus9.3%)andmorefrequentdosemodificationsforadversereactions(13.4%versus7.6%)inpatients65yearsorolderascomparedtothoseyoungerthan 65 years.

TAGRISSO® (osimertinib) tablets, for oral use 6

8.6 Renal ImpairmentNodose adjustment is recommended inpatientswith creatinine clearance (CLcr)15-89mL/min,asestimatedbyCockcroft-Gault.ThereisnorecommendeddoseofTAGRISSOforpatientswithend-stagerenaldisease(CLcr<15mL/min)[see Clinical Pharmacology (12.3)].

8.7 Hepatic ImpairmentNodose adjustment is recommended inpatientswithmild tomoderatehepaticimpairment(Child-PughAandBortotalbilirubin≤ULNandAST>ULNortotalbilirubin 1 to 3 times ULN and any AST). There is no recommended dose forTAGRISSO for patients with severe hepatic impairment (total bilirubin between 3to10timesULNandanyAST)[see Clinical Pharmacology (12.3)].

11 DESCRIPTIONOsimertinibisakinaseinhibitorfororaluse.Themolecularformulaforosimertinibmesylate 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.Osimertinibhasthefollowingstructuralformula(asosimertinibmesylate):

TAGRISSO tablets contain 40 or 80 mg of osimertinib, equivalent to 47.7 and 95.4mgofosimertinibmesylate,respectively.Inactiveingredientsinthetabletcorearemannitol,microcrystallinecellulose,low-substitutedhydroxpropylcelluloseandsodiumstearylfumarate.Thetabletcoatingconsistsofpolyvinylalcohol,titaniumdioxide,macrogol3350,talc,ferricoxideyellow,ferricoxideredandferricoxideblack.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionOsimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR),which binds irreversibly to certain mutant forms of EGFR (T790M, L858R, andexon 19 deletion) at approximately 9-fold lower concentrations than wild-type.Two pharmacologically-active metabolites (AZ7550 and AZ5104 circulating atapproximately10%oftheparent)withsimilarinhibitoryprofilestoosimertinibhavebeenidentifiedintheplasmaafteroraladministrationofosimertinib.AZ7550showedasimilarpotencytoosimertinib,whileAZ5104showedgreaterpotencyagainstexon19deletionandT790Mmutants(approximately8-fold)andwild-type(approximately15-fold)EGFR.In vitro,osimertinibalsoinhibitedtheactivityofHER2,HER3,HER4,ACK1,andBLKatclinicallyrelevantconcentrations.In cultured cells and animal tumor implantation models, osimertinib exhibited anti-tumoractivityagainstNSCLClinesharboringEGFR-mutations(T790M/L858R,L858R, T790M/exon 19 deletion, and exon 19 deletion) and, to a lesser extent, wild-typeEGFRamplifications.Osimertinibdistributedtothebraininmultipleanimalspecies(monkey,rat,andmouse)withbraintoplasmaAUCratiosofapproximately2 following oral dosing. These data are consistent with observations of tumorregressionandincreasedsurvivalinosimertinib-versuscontrol-treatedanimalsinapre-clinicalmutant-EGFRintracranialmousemetastasisxenograftmodel(PC9;exon19deletion).

12.2 PharmacodynamicsBasedonananalysisofdose-exposureresponserelationshipsoverthedoserangeof 20 mg (0.25 times the recommended dose) to 240 mg (3 times the recommended dose),noapparentrelationshipbetweenosimertinibexposureandoverallresponserate, duration of response and progression-free survival was identified; however,there were limited data available at the 20 mg dose. Over the same dose range,increased exposure led to increased probability of adverse reactions, specificallyrash,diarrheaandILD.

CardiacElectrophysiologyTheQTcintervalprolongationpotentialofosimertinibwasassessedin210patientswho received TAGRISSO 80 mg daily in AURA2. A central tendency analysis oftheQTcFdataatsteady-statedemonstratedthatthemaximummeanchangefrombaselinewas16.2msec (upperboundof two-sided90%confidence interval (CI)17.6 msec). A pharmacokinetic/pharmacodynamic analysis in AURA2 suggested aconcentration-dependentQTc intervalprolongationof14msec (upperboundoftwo-sided90%CI:16msec)atadoseofTAGRISSO80mg.

12.3 PharmacokineticsThe area under the plasma concentration-time curve (AUC) and maximal plasmaconcentration(Cmax)ofosimertinibincreaseddoseproportionallyover20to240mgdoserange(i.e.,0.25to3timestherecommendeddosage)afteroraladministrationandexhibitedlinearpharmacokinetics(PK).AdministrationofTAGRISSOorallyoncedaily resulted in approximately 3-fold accumulation with steady-state exposuresachieved after 15 days of dosing. At steady state, the Cmax to Cmin (minimalconcentration)ratiowas1.6-fold.

AbsorptionThemediantimetoCmaxofosimertinibwas6hours(range3-24hours).Followingadministrationofa20mgTAGRISSOtabletwithahigh-fat,high-caloriemeal (containingapproximately58gramsof fat and1000calories), theCmax and AUCofosimertinibwerecomparabletothatunderfastingconditions.

DistributionThemeanvolumeofdistributionatsteady-state (Vss/F)ofosimertinibwas918L.Plasmaproteinbindingofosimertinibwas95%.

EliminationOsimertinibplasmaconcentrationsdecreasedwithtimeandapopulationestimatedmeanhalf-lifeofosimertinibwas48hours,andoralclearance(CL/F)was14.3(L/h).

MetabolismThemainmetabolicpathwaysofosimertinibwereoxidation(predominantlyCYP3A)and dealkylation in vitro. Two pharmacologically active metabolites (AZ7550 andAZ5104) have been identified in the plasma after TAGRISSO oral administration.Thegeometricmeanexposure(AUC)ofeachmetabolite(AZ5104andAZ7550)wasapproximately10%oftheexposureofosimertinibatsteady-state.

ExcretionOsimertinib is primarily eliminated in the feces (68%) and to a lesser extent inthe urine (14%). Unchanged osimertinib accounted for approximately 2% of theelimination.

SpecificPopulationsNo clinically significant differences in the pharmacokinetics of osimertinib wereobservedbasedonage,sex,ethnicity,bodyweight,baselinealbumin,lineoftherapy,smokingstatus,renalfunction(creatinineclearance(CLcr)≥15mL/minbyCockcroft-Gault), or hepatic impairment (Child-Pugh A and B, or total bilirubin ≤ ULN and AST > ULN or total bilirubin between 1 to 3 times ULN and any AST). Thepharmacokinetics of osimertinib in patients with end-stage renal disease (CLcr<15mL/min)orseverehepaticimpairment(totalbilirubin3to10timesULNandanyAST)areunknown[see Use in Specific Populations (8.6) and (8.7)].

Drug Interaction Studies

Effect of Other Drugs on TAGRISSO in Clinical Pharmacokinetic Studies Strong CYP3A Inducers: Thesteady-stateAUCofosimertinibwasreducedby78%inpatientswhenco-administeredwithrifampin(600mgdailyfor21days)[see Drug Interactions (7.1)].Strong CYP3A Inhibitors: Co-administering TAGRISSO with 200 mg itraconazoletwice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on theexposureofosimertinib(AUCincreasedby24%andCmax decreased by 20%).Gastric Acid Reducing Agents: The exposure of osimertinib was not affected byconcurrent administration of a single 80 mg TAGRISSO tablet following 40 mgomeprazoleadministrationfor5days.

Effect of Osimertinib on Other Drugs in Clinical Pharmacokinetic StudiesBCRP substrates:Co-administeringTAGRISSOwithrosuvastatin(aBCRPsubstrate)increasedrosuvastatinAUCby35%andCmax by 72% [see Drug Interactions (7.2)].P-gp substrates:Co-administeringTAGRISSOwithfexofenadine(aP-gpsubstrate)increasedfexofenadineAUCandCmaxby56%and76%afterasingledoseand27%and25%atsteadystate,respectively.CYP3A4 substrates: Co-administering TAGRISSO with simvastatin (a CYP3A4substrate)hadnoclinicallysignificanteffectontheexposureofsimvastatin.

In Vitro StudiesCYP450 Metabolic Pathways:OsimertinibdoesnotinhibitCYP1A2,2A6,2B6,2C8,2C9,2C19,2D6and2E1.OsimertinibinducedCYP1A2enzymes.Transporter Systems:OsimertinibisasubstrateofP-glycoproteinandBCRPandisnotasubstrateofOATP1B1andOATP1B3.OsimertinibisaninhibitorofBCRPanddoesnotinhibitOAT1,OAT3,OATP1B1,OATP1B3,MATE1,MATE2KandOCT2.

TAGRISSO® (osimertinib) tablets, for oral use

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenicitystudieshavenotbeenperformedwithosimertinib.Osimertinibdidnot cause genetic damage in in vitro and in vivo assays.Based on studies in animals, male fertility may be impaired by treatment withTAGRISSO. Degenerative changes were present in the testes in rats and dogsexposedtoosimertinibfor1monthormorewithevidenceofreversibilityintherat.Followingadministrationofosimertinibtoratsforapproximately10weeksatadoseof40mg/kg,atexposures0.5timestheAUCobservedattherecommendedclinicaldoseof80mgoncedaily,therewasareductioninmalefertility,demonstratedbyincreasedpre-implantationlossinuntreatedfemalesmatedtotreatedmales.Based on studies in animals, female fertility may be impaired by treatment withTAGRISSO.Inrepeatdosetoxicitystudies,histologicalevidenceofanestrus,corporalutea degeneration in the ovaries and epithelial thinning in the uterus and vaginawereseeninratsexposedtoosimertinibfor1monthormoreatexposures0.3timestheAUCobservedattherecommendedclinicaldoseof80mgoncedaily.Findingsintheovariesseenfollowing1monthofdosingexhibitedevidenceofreversibility.Inafemalefertilitystudyinrats,administrationofosimertinibfrom2weekspriorto mating through Day 8 of gestation at a dose of 20 mg/kg/day (approximately1.5timestheCmaxat therecommendeddoseof80mgoncedaily)hadnoeffectsonoestruscyclingorthenumberoffemalesbecomingpregnant,butcausedearlyembryonic deaths. These findings showed evidence of reversibility when femalesweremated1monthaftertreatmentdiscontinuation.

14 CLINICAL STUDIES

14.1 Previously Untreated EGFR Mutation-Positive Metastatic Non-Small Cell Lung CancerTheefficacyofTAGRISSOwasdemonstrated ina randomized,multicenter,double-blind,active-controlledtrial(FLAURA[NCT02296125])inpatientswithEGFRexon19deletionorexon21L858Rmutation-positive,metastaticNSCLC,whohadnotreceivedprevious systemic treatment formetastatic disease.Patientswere required to havemeasurablediseaseperRECISTv1.1,aWHOperformancestatusof0-1,andEGFRexon19deletionorexon21L858Rmutationintumorprospectivelyidentifiedbythecobas®EGFRMutationTestinacentrallaboratoryorbyaninvestigationalassayataCLIA-certified or accredited laboratory. Patients with CNS metastases not requiringsteroids and with stable neurologic status for at least two weeks after completionof definitive surgery or radiotherapy were eligible. Patients were assessed at theinvestigator’sdiscretionforCNSmetastasesiftheyhadahistoryof,orsuspected,CNSmetastases at study entry.Patientswererandomized(1:1)toreceiveTAGRISSO80mgorallyoncedailyortoreceivegefitinib250mgorallyoncedailyorerlotinib150mgorallyoncedailyuntildiseaseprogressionorunacceptabletoxicity.RandomizationwasstratifiedbyEGFRmutationtype(exon19deletionorexon21L858Rmutation)andethnicity(Asianornon-Asian).PatientsrandomizedtothecontrolarmwereofferedTAGRISSOatthetimeofdiseaseprogressioniftumorsamplestestedpositivefortheEGFRT790Mmutation.Themajorefficacyoutcomemeasurewasprogression-freesurvival(PFS),asassessedbyinvestigator.Additionalefficacyoutcomemeasuresincludedoverallsurvival(OS)andoverallresponserate(ORR).Atotalof556patientswererandomizedtoTAGRISSO(n=279)ortocontrol(gefitinibn=183;erlotinibn=94).Themedianagewas64years(range26-93years);54%were<65yearsofage;63%werefemale;62%wereAsianand64%wereneversmokers.Baseline WHO performance status was 0 (41%) or 1 (59%); 5% had Stage IIIband95%hadStageIV;and7%receivedpriorsystemiccytotoxicchemotherapyasneoadjuvantoradjuvanttherapy.WithregardtoEGFRtumortesting,63%wereexon19deletionand37%wereexon21L858R;5patients(

TAGRISSO® (osimertinib) tablets, for oral use

Figure 2. Kaplan-Meier Curves of Overall Survival in FLAURA

Of 556 patients, 200 patients (36%) had baseline brain scans reviewed by BICR; thisincluded106patientsintheTAGRISSOarmand94patientsintheinvestigatorchoice of EGFR TKI arm. Of these 200 patients, 41 had measurable CNS lesionsper RECIST v1.1. Results of pre-specified exploratory analyses of CNS ORR andDoRbyBICRinthesubsetofpatientswithmeasurableCNSlesionsatbaselinearesummarizedinTable7.

Table 7. CNS ORR and DOR by BICR in Patients with Measurable CNS Lesions at Baseline in FLAURA

TAGRISSON=22

EGFR TKI(gefitinib or erlotinib)

N=19

CNS Tumor Response Assessment*,†

CNSORR,%(95%CI) 77% (55, 92) 63% (38, 84)

Completeresponse 18% 0%

Duration of CNS Response‡

Numberofresponders 17 12

ResponseDuration≥6 months 88% 50%

ResponseDuration≥12 months 47% 33%

*AccordingtoRECISTv1.1.† Basedonconfirmedresponse.‡ Basedonpatientswithresponseonly;DoRdefined asthetimefromthedateoffirstdocumented

response(completeresponseorpartialresponse)untilprogressionordeathevent.

14.2 Previously Treated EGFR T790M Mutation-Positive Metastatic Non-Small Cell Lung CancerThe efficacy of TAGRISSO was demonstrated in a randomized, multicenter open-label, active-controlled trial in patients with metastatic EGFR T790M mutation-positiveNSCLCwhohadprogressedonpriorsystemictherapy,includinganEGFRTKI(AURA3).Allpatientswererequired tohaveEGFRT790Mmutation-positiveNSCLCidentifiedbythecobas®EGFRMutationTestperformedinacentrallaboratorypriortorandomization.A total of 419 patients were randomized 2:1 to receive TAGRISSO (n=279) orplatinum-based doublet chemotherapy (n=140). Randomization was stratified byethnicity(Asianvs.non-Asian).PatientsintheTAGRISSOarmreceivedTAGRISSO 80 mg orally once daily until intolerance to therapy, disease progression, orinvestigatordeterminationthatthepatientwasnolongerbenefitingfromtreatment.Patientsinthechemotherapyarmreceivedpemetrexed500mg/m2withcarboplatinAUC5orpemetrexed500mg/m2withcisplatin75mg/m2onDay1ofevery21-daycycleforupto6cycles.Patientswhosediseasehadnotprogressedafterfourcyclesof platinum-based chemotherapy could have received pemetrexed maintenancetherapy(pemetrexed500mg/m2onDay1ofevery21-daycycle).Themajorefficacyoutcomemeasurewasprogression-freesurvival(PFS)accordingto Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by investigatorassessment.Additionalefficacyoutcomemeasures includedoverall response rate(ORR),durationofresponse(DoR),andoverallsurvival(OS).Patientsrandomizedto the chemotherapy arm who had radiological progression according to bothinvestigatorandblindedindependentcentralreview(BICR)werepermittedtocrossovertoreceivetreatmentwithTAGRISSO.

Thebaselinedemographicanddiseasecharacteristicsoftheoveralltrialpopulationwere:medianage62years(range:20-90years),≥75yearsold(15%),female(64%),White(32%),Asian(65%),neversmoker(68%),WHOperformancestatus0or1(100%).Fifty-fourpercent(54%)ofpatientshadextra-thoracicvisceralmetastases,including34%withcentralnervoussystem(CNS)metastases(including11%withmeasurable CNS metastases) and 23% with liver metastases. Forty-two percent(42%)ofpatientshadmetastaticbonedisease.InAURA3, therewasastatisticallysignificant improvement inPFS in thepatientsrandomizedtoTAGRISSOcomparedtochemotherapy(SeeTable8andFigure3).OverallsurvivaldatawerenotmatureatthetimeofthePFSanalysis.

Table 8. Efficacy Results According to Investigator Assessment in AURA3

Efficacy Parameter TAGRISSO

(N=279)

Chemotherapy

(N=140)

Progression-Free Survival

Numberofevents(%) 140 (50) 110 (79)

Progressivedisease 129 (46) 104 (74)

Death* 11 (4) 6 (4)

MedianPFSinmonths(95%CI) 10.1 (8.3, 12.3) 4.4 (4.2, 5.6)

HazardRatio(95%CI)†, ‡ 0.30 (0.23,0.41)

P-value†, §

TAGRISSO® (osimertinib) tablets, for oral use

Of419patients,205(49%)hadbaselinebrainscansreviewedbyBICR;thisincluded134(48%)patientsintheTAGRISSOarmand71(51%)patientsinthechemotherapyarm.AssessmentofCNSefficacybyRECISTv1.1wasperformedinthesubgroupof46/419(11%)patientsidentifiedbyBICRtohavemeasurableCNSlesionsonabaselinebrainscan.ResultsaresummarizedinTable9.

Table 9. CNS ORR and DoR by BICR in Patients with Measurable CNS Lesions at Baseline in AURA3

TAGRISSO

N=30

Chemotherapy

N=16

CNS Tumor Response Assessment*,†

CNSORR,%(95%CI) 57% (37, 75) 25% (7, 52)

Completeresponse 7% 0

Duration of CNS Response†,‡

Numberofresponders 17 4

ResponseDuration≥ 6 months 47% 0

ResponseDuration≥ 9 months 12% 0

*AccordingtoRECISTv1.1.† Basedonconfirmedresponse.‡ Basedonpatientswithresponseonly;DoRdefined asthetimefromthedateoffirstdocumented

response(completeresponseorpartialresponse)untilprogressionordeathevent.

16 HOW SUPPLIED/STORAGE AND HANDLING

80mgtablets:beige,ovalandbiconvextabletmarkedwith“AZ80”ononesideandplainonthereverseandareavailableinbottlesof30(NDC0310-1350-30).

40mgtablets:beige,roundandbiconvextabletmarkedwith“AZ40”ononesideandplainonthereverseandareavailableinbottlesof30(NDC0310-1349-30).

StoreTAGRISSObottlesat25°C(77°F).Excursionspermittedto15-30°C(59-86°F)[seeUSPControlledRoomTemperature].

17 PATIENT COUNSELING INFORMATION

AdvisethepatienttoreadtheFDA-approvedpatientlabeling(PatientInformation).

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

prolongationincludingdizziness,lightheadedness,andsyncope.Advisepatientstoreport thesesymptomsandto informtheirphysicianabout theuseofanyheartorbloodpressuremedications[see Warnings and Precautions (5.2)].

9

Cardiomyopathy• InformpatientsthatTAGRISSOcancausecardiomyopathy.Advisepatientsto

immediatelyreportanysignsorsymptomsofheart failure to theirhealthcareprovider[see Warnings and Precautions (5.3)].

Keratitis• Advise patients to contact their healthcare provider immediately if they develop

eye symptoms (eye inflammation, lacrimation, light sensitivity, eye pain, red eye or changes in vision) [see Warnings and Precautions (5.4)].

ErythemamultiformeandStevens-Johnsonsyndrome• Informpatientsofsignsandsymptomsthatmaybe indicativeofEMorSJS.

Advisepatientstocontacttheirhealthcareproviderimmediatelyiftheydeveloptarget lesions or severe blistering or peeling of skin. [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity• Advisepregnantwomenandfemalesofreproductivepotentialofthepotential

risktoafetus.Advisefemalestoinformtheirhealthcareprovideriftheybecomepregnantor ifpregnancyissuspected,whiletakingTAGRISSO[see Warnings and Precautions (5.6) 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)].

• Advisemalestouseeffectivecontraceptionduringtreatmentandfor4monthsafterthefinaldoseofTAGRISSO[see Use in Specific Populations (8.3)].

LactationAdvise women not to breastfeed during treatment with TAGRISSO and for 2 weeks after the final dose [see Use in Specific Populations (8.2)].

Distributed by: AstraZenecaPharmaceuticalsLP Wilmington,DE19850

TAGRISSOisaregisteredtrademarkoftheAstraZenecagroupofcompanies.

©AstraZeneca2020

Rev.06/20US-417786/20

TAGRISSO® (osimertinib) tablets, for oral use 10

Patient InformationTAGRISSO® (tuh-GRISS-oh)

(osimertinib)tablets

What is the most important information I should know about TAGRISSO?TAGRISSO may cause serious side effects, including:• lung problems. TAGRISSOmaycauselungproblemsthatmayleadtodeath.Symptomsmaybesimilartothosesymptomsfrom

lungcancer.Tellyourdoctorrightawayifyouhaveanyneworworseninglungsymptoms,includingtroublebreathing,shortnessofbreath,cough,orfever.

• heart problems, including heart failure. TAGRISSOmaycauseheartproblemsthatmayleadtodeath.Yourdoctorshouldcheckyour heart function before you start taking TAGRISSO andduringtreatmentasneeded.Tellyourdoctorrightawayifyouhaveanyofthefollowingsignsandsymptomsofaheartproblem:feelinglikeyourheartispoundingorracing,shortnessofbreath,swellingofyouranklesandfeet,feelinglightheaded.

• eye problems. TAGRISSOmaycauseeyeproblems.Tellyourdoctorrightawayifyouhavesymptomsofeyeproblemswhichmayincludewateryeyes,sensitivitytolight,eyepain,eyeredness,orvisionchanges.Yourdoctormaysendyoutoseeaneyespecialist(ophthalmologist)ifyougeteyeproblemswithTAGRISSO.

• skin problems. TAGRISSOmaycauseskinproblems.Tellyourdoctorrightawayifyoudeveloptargetlesions(skinreactionsthatlooklikerings),severeblisteringorpeelingoftheskin.

See “What are the possible side effects of TAGRISSO?” for more information about side effects.

What is TAGRISSO?TAGRISSOisaprescriptionmedicineusedtotreatnon-smallcelllungcancer(NSCLC)thathasspreadtootherpartsofthebody (metastatic):

• asyourfirsttreatmentifyourtumorhasacertainabnormalepidermalgrowthfactorreceptor(EGFR)gene(s)or

• ifyouhaveacertaintypeofEGFRgeneandhadprevioustreatmentwithanEGFRtyrosinekinaseinhibitor(TKI) medicinethatdidnotworkorisnolongerworking.

YourdoctorwillperformatesttomakesurethatTAGRISSOisrightforyou.ItisnotknownifTAGRISSOissafeandeffectiveinchildren.

Before taking TAGRISSO, tell your doctor about all of your medical conditions, including if you:• havelungorbreathingproblems.• haveheartproblems,includingaconditioncalledlongQTcsyndrome.• haveproblemswithyourelectrolytes,suchassodium,potassium,calciumormagnesium.• haveahistoryofeyeproblems.• arepregnantorplantobecomepregnant.TAGRISSOcanharmyourunbornbaby.Tellyourdoctorrightawayifyoubecome

pregnantduringtreatmentwithTAGRISSOorthinkyoumaybepregnant.

° Females whoareabletobecomepregnantshoulduseeffectivebirthcontrolduringtreatmentwithTAGRISSOandfor 6weeksafterthefinaldoseofTAGRISSO.

° Males whohavefemalepartnersthatareabletobecomepregnantshoulduseeffectivebirthcontrolduringtreatmentwithTAGRISSOandfor4monthsafterthefinaldoseofTAGRISSO.

• arebreastfeedingorplantobreastfeed.It isnotknownif TAGRISSOpassesintoyourbreastmilk.DonotbreastfeedduringtreatmentwithTAGRISSOandfor2weeksafteryourfinaldoseofTAGRISSO.Talktoyourdoctoraboutthebestwaytofeedyourbaby during this time.

Tellyourdoctoraboutallthemedicinesyoutake,includingprescriptionandover-the-countermedicines,vitamins,orherbalsupplements.Especiallytellyourdoctorifyoutakeaheartorbloodpressuremedicine.

TAGRISSO® (osimertinib) tablets, for oral use 11

How should I take TAGRISSO?• TakeTAGRISSOexactlyasyourdoctortellsyoutotakeit.• Yourdoctormaychangeyourdose,temporarilystop,orpermanentlystoptreatmentwithTAGRISSOifyouhavesideeffects.• TakeTAGRISSO1timeeachday.• YoucantakeTAGRISSOwithorwithoutfood.• IfyoumissadoseofTAGRISSO,donotmakeupforthemisseddose.Takeyournextdoseatyourregulartime.• If you cannot swallow TAGRISSO tablets whole:

° placeyourdoseofTAGRISSOinacontainerthatcontains60mL(2ounces)ofwater.Donotusecarbonatedwateroranyotherliquids.

° stirtheTAGRISSOtabletandwateruntiltheTAGRISSOtabletisinsmallpieces(thetabletwillnotcompletelydissolve). Donotcrush,heat,oruseultrasoundtopreparethemixture.

° drinktheTAGRISSOandwatermixturerightaway.° add120mLto240mL(4to8ounces)ofwaterintothecontaineranddrinktomakesurethatyoutakeyourfulldoseofTAGRISSO.

What are the possible side effects of TAGRISSO? TAGRISSO may cause serious side effects, including:•See“What is the most important information I should know about TAGRISSO?”•Severeblisteringorpeelingofskin–seekmedicalattentionrightawayifyoudevelopthesesymptoms.•Targetlesions,whichareskinreactionsthatlooklikerings–seekmedicalattentionrightawayifyoudevelopthesesymptoms.The most common side effects of TAGRISSO are:

• diarrhea •mouthsores• rash •tiredness • dryskin •decreasedappetite•changesinyournails,including:redness,tenderness,pain,inflammation,brittleness,separationfromnailbed,andsheddingofnails

Tellyourdoctorifyouhaveanysideeffectthatbothersyouorthatdoesnotgoaway.ThesearenotallthepossiblesideeffectsofTAGRISSO.Formoreinformation,askyourdoctororpharmacist.Callyourdoctorformedicaladviceaboutsideeffects.YoumayreportsideeffectstoFDAat1-800-FDA-1088.

How should I store TAGRISSO?• StoreTAGRISSOatroomtemperaturebetween68°Fto77°F(20°Cto25°C).• Safelythrowawaymedicinethatisoutofdateorthatyounolongerneed.• Keep TAGRISSO and all medicines out of the reach of children.

General information about the safe and effective use of TAGRISSO.• MedicinesaresometimesprescribedforpurposesotherthanthoselistedinaPatientInformationleaflet.DonotuseTAGRISSO

foraconditionforwhichitwasnotprescribed.DonotgiveTAGRISSOtootherpeople,eveniftheyhavethesamesymptomsyouhave.Itmayharmthem.YoucanaskyourdoctororpharmacistforinformationaboutTAGRISSOthatiswrittenforahealthcareprofessional.

What are the ingredients in TAGRISSO? Active ingredient: osimertinibInactive ingredients: mannitol,microcrystallinecellulose,low-substitutedhydroxypropylcellulose,andsodiumstearylfumarate.Tabletcoatingcontains:polyvinylalcohol,titaniumdioxide,macrogol3350,talc,ferricoxideyellow,ferricoxideredandferricoxideblack.Formoreinformation,gotowww.Tagrisso.comorcall1-800-236-9933.Distributedby:AstraZenecaPharmaceuticalsLP,Wilmington,DE19850©AstraZeneca2020

ThisPatientInformationhasbeenapprovedbytheU.S.FoodandDrugAdministration.Revised:05/2020US-417786/20

1 INDICATIONS AND USAGE1.1 First-line Treatment of EGFR Mutation-Positive Metastatic Non-Small CellLung Cancer (NSCLC)1.2 Previously Treated EGFR T790M Mutation-Positive Metastatic NSCLC

2 DOSAGE AND ADMINISTRATION2.1 Patient Selection2.2 Recommended Dosage Regimen2.3 Administration to Patients Who Have Difficulty Swallowing Solids2.4 Dosage Modifications

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Interstitial Lung Disease/Pneumonitis5.2 QTc Interval Prolongation5.3 Cardiomyopathy5.4 Keratitis5.5 Erythema Multiforme and Stevens-Johnson Syndrome5.6 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Postmarketing Experience

7 DRUG INTERACTIONS7.1 Effect of Other Drugs on Osimertinib7.2 Effect of Osimertinib on Other Drugs7.3 Drugs That Prolong the QTc Interval

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Lactation8.3 Females and Males of Reproductive Potential8.4 Pediatric Use8.5 Geriatric Use8.6 Renal Impairment8.7 Hepatic Impairment

11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES14.1 Previously Untreated EGFR Mutation-Positive Metastatic Non-Small CellLung Cancer14.2 Previously Treated EGFR T790M Mutation-Positive Metastatic Non-SmallCell Lung Cancer

16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATIONPatient Information