TAGRISSO 80mg tablets medication leaflet

TAGRISSO 40 mg film-coated tablets

TAGRISSO 80 mg film-coated tablets

TAGRISSO 40 mg tablets

Each tablet contains 40 mg osimertinib (as mesylate).

TAGRISSO 80 mg tablets

Each tablet contains 80 mg osimertinib (as mesylate).

TAGRISSO 40 mg tablets

Each tablet contains 0.3 mg sodium.

TAGRISSO 80 mg tablets

Each tablet contains 0.6 mg sodium.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

TAGRISSO 40 mg tablets

Beige, 9 mm, round, biconvex tablet, debossed with “AZ” and “40” on one side and plain on thereverse.

TAGRISSO 80 mg tablets

Beige, 7.25 x 14.5 mm, oval, biconvex tablet, debossed with “AZ” and “80” on one side and plain onthe reverse.

TAGRISSO as monotherapy is indicated for:

* the adjuvant treatment after complete tumour resection in adult patients with stage IB-IIIA non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR)exon 19 deletions or exon 21 (L858R) substitution mutations (see section 5.1).

* the treatment of adult patients with locally advanced, unresectable NSCLC whose tumours have

EGFR exon 19 deletions or exon 21 (L858R) substitution mutations and whose disease has notprogressed during or following platinum-based chemoradiation therapy.

* the first-line treatment of adult patients with locally advanced or metastatic NSCLC withactivating EGFR mutations.

* the treatment of adult patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.

TAGRISSO is indicated in combination with:

* pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients withadvanced NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R)substitution mutations.

Treatment with TAGRISSO should be initiated by a physician experienced in the use of anticancertherapies.

When considering the use of TAGRISSO, EGFR mutation status (in tumour specimens for adjuvanttreatment or for treatment of locally advanced, unresectable tumours and tumour or plasma specimensfor locally advanced or metastatic setting) should be determined using a validated test method (seesection 4.4).

The recommended dose is 80 mg osimertinib once a day.

The recommended dose of TAGRISSO is 80 mg osimertinib once a day when taken with pemetrexedand platinum-based chemotherapy.

Refer to the Summary of Product Characteristics for pemetrexed and cisplatin or carboplatin for therespective dosing information.

Patients in the adjuvant setting should receive treatment until disease recurrence or unacceptabletoxicity. Treatment duration for more than 3 years was not studied.

Patients with locally advanced or metastatic lung cancer should receive TAGRISSO treatment untildisease progression or unacceptable toxicity.

If a dose of TAGRISSO is missed, the dose should be made up unless the next dose is due within12 hours.

TAGRISSO can be taken with or without food at the same time each day.

Dosing interruption and/or dose reduction may be required based on individual safety and tolerability.

If dose reduction is necessary, then the dose should be reduced to 40 mg taken once daily.

Dose reduction guidelines for adverse reactions toxicities are provided in Table 1.

Table 1. Recommended dose modifications for TAGRISSO

Target organ Adverse reactiona Dose modification

Pulmonaryb ILD/Pneumonitisc Permanently discontinue TAGRISSO

Grade 1 Radiation Pneumonitis Consider withholding or continue

TAGRISSO, as clinically indicated

Grade 2 Radiation Pneumonitis Withhold TAGRISSO until symptomsresolve. TAGRISSO may be restarted.

Permanently discontinue if symptomsdo not resolve after 4 weeks or Grade2 Radiation Pneumonitis recurs

Grade 3 or 4 Radiation Permanently discontinue TAGRISSO

Pneumonitis

Cardiacb QTc interval greater than Withhold TAGRISSO until QTc500 msec on at least 2 separate interval is less than 481 msec or

ECGs recovery to baseline if baseline QTc isgreater than or equal to 481 msec, thenrestart at a reduced dose (40 mg)

QTc interval prolongation with Permanently discontinue TAGRISSOsigns/symptoms of seriousarrhythmia

Cutaneousb Stevens-Johnson Syndrome and Permanently discontinue TAGRISSO

Toxic epidermal necrolysis

Blood and lymphatic Aplastic anaemia Permanently discontinue TAGRISSOsystemb

Other Grade 3 or higher adverse Withhold TAGRISSO for up to 3reaction weeks

If Grade 3 or higher adverse TAGRISSO may be restarted at thereaction improves to Grade 0-2 same dose (80 mg) or a lower doseafter withholding of (40 mg)

TAGRISSO for up to 3 weeks

Grade 3 or higher adverse Permanently discontinue TAGRISSOreaction that does not improveto Grade 0-2 after withholdingfor up to 3 weeksa Note: The intensity of clinical adverse events graded by the National Cancer Institute (NCI) Common

Terminology Criteria for Adverse Events (CTCAE) version 5.0.b Refer to section 4.4.c ILD/Pneumonitis including ILD/Pneumonitis following definitive platinum-based chemoradiation therapy.

ECGs: Electrocardiograms; QTc: QT interval corrected for heart rate

When TAGRISSO is used in combination, any of the treatment components should be dose modified,as appropriate. For TAGRISSO dose modification instructions, see Table 1. The pemetrexed, cisplatinor carboplatin dose should be modified in accordance with the instructions in their respective

Summary of Product Characteristics. Cisplatin and/or carboplatin should be used for up to 4 cycles.

No dose adjustment is required due to patient age, body weight, gender, ethnicity and smoking status(see section 5.2).

Based on clinical studies, no dose adjustments are necessary in patients with mild hepatic impairment(Child Pugh A) or moderate hepatic impairment (Child Pugh B). Similarly, based on populationpharmacokinetic analysis, no dose adjustment is recommended in patients with mild hepaticimpairment (total bilirubin ≤upper limit of normal (ULN) and aspartate aminotransferase (AST)>ULN or total bilirubin >1.0 to 1.5 times ULN and any AST) or moderate hepatic impairment (totalbilirubin between 1.5 to 3 times ULN and any AST). The safety and efficacy of this medicinal producthas not been established in patients with severe hepatic impairment. Until additional data becomeavailable, use in patients with severe hepatic impairment is not recommended (see section 5.2).

Based on clinical studies and population PK analysis, no dose adjustments are necessary in patientswith mild, moderate, or severe renal impairment. The safety and efficacy of this medicinal product hasnot been established in patients with end-stage renal disease [creatinine clearance (CLcr) less than15 mL/min, calculated by the Cockcroft and Gault equation], or on dialysis. Caution should beexercised when treating patients with severe and end-stage renal impairment (see section 5.2).

The safety and efficacy of TAGRISSO in children or adolescents aged less than 18 years have notbeen established. No data are available.

This medicinal product is for oral use. The tablet should be swallowed whole with water and it shouldnot be crushed, split or chewed.

If the patient is unable to swallow the tablet, the tablet may first be dispersed in 50 mL ofnon-carbonated water. It should be dropped in the water, without crushing, stirred until dispersed andimmediately swallowed. An additional half a glass of water should be added to ensure that no residueremains and then immediately swallowed. No other liquids should be added.

If administration via nasogastric tube is required, the same process as above should be followed butusing volumes of 15 mL for the initial dispersion and 15 mL for the residue rinses. The resulting30 mL of liquid should be administered as per the nasogastric tube manufacturer’s instructions withappropriate water flushes. The dispersion and residues should be administered within 30 minutes ofthe addition of the tablets to water.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

St. John’s Wort should not be used together with TAGRISSO (see section 4.5).

Assessment of EGFR mutation status

When considering the use of TAGRISSO as adjuvant treatment after complete tumour resection inpatients with NSCLC, EGFR mutation positive status (exon 19 deletions [Ex19del] or exon 21 L858Rsubstitution mutations [L858R]) indicates treatment eligibility. A validated test should be performed ina clinical laboratory using tumour tissue DNA from biopsy or surgical specimen.

When considering the use of TAGRISSO in patients with locally advanced, unresectable NSCLC andwhose disease has not progressed during or following platinum-based chemoradiation therapy, EGFRmutation positive status (exon 19 deletions or exon 21 [L858R] substitution mutations) indicatestreatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue

DNA from a biopsy specimen.

When considering the use of TAGRISSO as a treatment for locally advanced or metastatic NSCLC, itis important that the EGFR mutation positive status is determined. A validated test should beperformed using either tumour DNA derived from a tissue sample or circulating tumour DNA(ctDNA) obtained from a plasma sample.

Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment,exon 19 deletion or exon 21 (L858R) substitution mutations when TAGRISSO is given in combinationwith pemetrexed and platinum-based chemotherapy for first-line treatment, or T790M mutationsfollowing progression on or after EGFR TKI therapy) using either a tissue-based or plasma-based test,indicates eligibility for treatment with TAGRISSO. However, if a plasma-based ctDNA test is usedand the result is negative, it is advisable to follow-up with a tissue test wherever possible due to thepotential for false negative results using a plasma-based test.

Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFRmutation status should be used.

Interstitial Lung Disease (ILD)

Severe, life-threatening or fatal ILD or ILD-like adverse reactions (e.g. pneumonitis) have beenobserved in patients treated with TAGRISSO in clinical studies, including TAGRISSO followingdefinitive platinum-based chemoradiation therapy. Most cases improved or resolved with interruptionof treatment. Patients with a past medical history of ILD, drug-induced ILD, radiation pneumonitisthat required steroid treatment, or any evidence of clinically active ILD, were excluded from clinicalstudies (see section 4.8).

Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonarysymptoms (dyspnoea, cough, fever) should be performed to exclude ILD. Treatment with thismedicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed,

TAGRISSO should be discontinued and appropriate treatment initiated as necessary. Reintroduction of

TAGRISSO should be considered only after careful consideration of the individual patient’s benefitsand risk.

Radiation pneumonitis

Radiation pneumonitis is usually observed for up to a year after patients receive radiation therapy tothe lungs. For TAGRISSO dose modification guidance for radiation pneumonitis following definitiveplatinum-based chemoradiation therapy, refer to section 4.2.

Severe Cutaneous Adverse Reactions (SCARs)

Case reports of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have beenreported with frequency categories of rare and not known, respectively, in association with

TAGRISSO treatment. Before initiating treatment, patients should be advised of signs and symptomsof SJS and TEN. If signs and symptoms suggestive of SJS or TEN appear, TAGRISSO should beinterrupted. TAGRISSO should be discontinued immediately if SJS or TEN are diagnosed.

QTc interval prolongation

QTc interval prolongation occurs in patients treated with TAGRISSO. QTc interval prolongation maylead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. No

QTc related arrythmias were reported in ADAURA, LAURA, FLAURA, FLAURA2 or AURAstudies (see section 4.8). Patients with clinically important abnormalities in rhythm and conduction asmeasured by resting electrocardiogram (ECG) (e.g. QTc interval greater than 470 msec) wereexcluded from these studies (see section 4.8).

When possible, the use of TAGRISSO in patients with congenital long QT syndrome should beavoided. Periodic monitoring with electrocardiograms (ECGs) and electrolytes should be considered inpatients with congestive heart failure, electrolyte abnormalities, or those who are taking medicinalproducts that are known to prolong the QTc interval. Treatment should be withheld in patients whodevelop a QTc interval greater than 500 msec on at least 2 separate ECGs until the QTc interval is lessthan 481 msec or recovery to baseline if the QTc interval is greater than or equal to 481 msec, thenresume TAGRISSO at a reduced dose as described in Table 1. TAGRISSO should be permanentlydiscontinued in patients who develop QTc interval prolongation in combination with any of thefollowing: Torsade de pointes, polymorphic ventricular tachycardia, signs/symptoms of seriousarrhythmia.

Changes in cardiac contractility

Across clinical studies, left ventricular ejection fraction (LVEF) decreases greater than or equal to10 percentage points and a drop to less than 50% occurred in 4.2% (65/1557) of patients treated with

TAGRISSO monotherapy who had baseline and at least one follow-up LVEF assessment. In patientswith cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, includingan assessment of LVEF at baseline and during treatment, should be considered. In patients whodevelop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEFassessment should be considered. In an adjuvant placebo-controlled study (ADAURA), 1.5% (5/325)of patients treated with TAGRISSO and 1.5% (5/331) of patients treated with placebo experienced

LVEF decreases greater than or equal to 10 percentage points and a drop to less than 50%. In the

LAURA study, following platinum-based chemoradiation therapy, 3.0% (4/135) of patients treatedwith TAGRISSO and no patients treated with placebo, who had both a baseline and post-baseline

LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentage points and adrop to less than 50%. In the FLAURA2 study, 8.0% (21/262) of patients treated with TAGRISSO incombination with pemetrexed and platinum-based chemotherapy, who had baseline and at least onefollow-up LVEF assessment, experienced LVEF decreases greater than or equal to 10 percentagepoints and a drop to less than 50%.

Keratitis

Keratitis was reported in 0.6% (n=11) of the 1956 patients treated with TAGRISSO monotherapy inthe ADAURA, FLAURA, FLAURA2, LAURA and AURA studies. Patients presenting with signs andsymptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, lightsensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmologyspecialist (see section 4.2 Table 1).

Aplastic anaemia

Rare cases of aplastic anaemia, including fatal events, have been reported in association with

TAGRISSO treatment. Before initiating treatment, patients should be advised of signs and symptomsof aplastic anaemia including but not limited to persistent fever, bruising, bleeding, pallor, infectionand fatigue. If signs and symptoms suggestive of aplastic anaemia develop, close patient monitoringand drug interruption or discontinuation of TAGRISSO should be considered. TAGRISSO should bediscontinued in patients with confirmed aplastic anaemia (see section 4.2).

Age and body weight

Elderly patients (>65 years) or patients with low body weight (<50 kg) may be at increased risk ofdeveloping adverse events of Grade 3 or higher. Close monitoring is recommended in these patients(see section 4.8).

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

Strong CYP3A4 inducers can decrease the exposure of osimertinib. Osimertinib may increase theexposure of breast cancer resistant protein (BCRP) and P-glycoprotein (P-gp) substrates.

Active substances that may increase osimertinib plasma concentrations

In vitro studies have demonstrated that the Phase I metabolism of osimertinib is predominantly via

CYP3A4 and CYP3A5. In a clinical pharmacokinetic study in patients, co-administration with 200 mgitraconazole twice daily (a strong CYP3A4 inhibitor) had no clinically significant effect on theexposure of osimertinib (area under the curve (AUC) increased by 24% and Cmax decreased by 20%).

Therefore, CYP3A4 inhibitors are not likely to affect the exposure of osimertinib. Further catalysingenzymes have not been identified.

Active substances that may decrease osimertinib plasma concentrations

In a clinical pharmacokinetic study in patients, the steady-state AUC of osimertinib was reduced by78% when co-administered with rifampicin (600 mg daily for 21 days). Similarly, the exposure tometabolite AZ5104 decreased by 82% for the AUC and 78% for Cmax. It is recommended thatconcomitant use of strong CYP3A inducers (e.g. Phenytoin, rifampicin and carbamazepine) with

TAGRISSO should be avoided. Moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine,modafinil) may also decrease osimertinib exposure and should be used with caution or avoided whenpossible. There are no clinical data available to recommend a dose adjustment of TAGRISSO.

Concomitant use of St. John’s Wort is contraindicated (see section 4.3).

Effect of gastric acid reducing active substances on osimertinib

In a clinical pharmacokinetic study, co-administration of omeprazole did not result in clinicallyrelevant changes in osimertinib exposures. Gastric pH modifying agents can be concomitantly usedwith TAGRISSO without any restrictions.

Active substances whose plasma concentrations may be altered by TAGRISSO

Based on in vitro studies, osimertinib is a competitive inhibitor of BCRP transporters.

In a clinical PK study, co-administration of TAGRISSO with rosuvastatin (sensitive BCRP substrate)increased the AUC and Cmax of rosuvastatin by 35% and 72%, respectively. Patients takingconcomitant medicinal products with disposition dependent upon BCRP and with narrow therapeuticindex should be closely monitored for signs of changed tolerability of the concomitant medication as aresult of increased exposure whilst receiving TAGRISSO (see section 5.2).

In a clinical PK study, co-administration of TAGRISSO with simvastatin (sensitive CYP3A4substrate) decreased the AUC and Cmax of simvastatin by 9% and 23% respectively. These changes aresmall and not likely to be of clinical significance. Clinical PK interactions with CYP3A4 substrates areunlikely. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

In a clinical Pregnane X Receptor (PXR) interaction study, co-administration of TAGRISSO withfexofenadine (P-gp substrate) increased the AUC and Cmax of fexofenadine by 56% (90% CI 35, 79)and 76% (90% CI 49, 108) after a single dose and 27% (90% CI 11, 46) and 25% (90% CI 6, 48) atsteady-state, respectively. Patients taking concomitant medications with disposition dependent upon

P-gp and with narrow therapeutic index (e.g. digoxin, dabigatran, aliskiren) should be closelymonitored for signs of changed tolerability as a result of increased exposure of the concomitantmedication whilst receiving TAGRISSO (see section 5.2).

Women of childbearing potential should be advised to avoid becoming pregnant while receiving

TAGRISSO. Patients should be advised to use effective contraception for the following periods aftercompletion of treatment with this medicinal product: at least 2 months for females and 4 months formales. A risk for decreased exposure of hormonal contraceptives cannot be excluded.

There are no or limited amount of data from the use of osimertinib in pregnant women. Studies inanimals have shown reproductive toxicity (embryo lethality, reduced foetal growth, and neonataldeath, see section 5.3). Based on its mechanism of action and preclinical data, osimertinib may causefoetal harm when administered to a pregnant woman. TAGRISSO should not be used duringpregnancy unless the clinical condition of the woman requires treatment with osimertinib.

It is unknown whether osimertinib/metabolites are excreted in human milk. There is insufficientinformation on the excretion of osimertinib/metabolites in animal milk. However, osimertinib and itsmetabolites were detected in the suckling pups and there was poor pup growth and a reduction in pupsurvival (see section 5.3). A risk to the suckling child cannot be excluded. Breast-feeding should bediscontinued during treatment with TAGRISSO.

There are no data on the effect of TAGRISSO on human fertility. Results from animal studies haveshown that osimertinib has effects on male and female reproductive organs and could impair fertility(see section 5.3).

TAGRISSO has no or negligible influence on the ability to drive and use machines.

Studies in EGFR mutation-positive NSCLC patients

The safety of TAGRISSO as a monotherapy is based on pooled data from 1956 patients with EGFRmutation-positive non-small cell lung cancer. These patients received TAGRISSO at a dose of 80 mgdaily in five randomised Phase 3 studies (ADAURA, adjuvant; FLAURA, and FLAURA2(monotherapy arm) first line; LAURA (post platinum‑based chemoradiation therapy) and AURA3,second line only), two Phase 2 single-arm studies (AURAex and AURA2, second line or later) andone Phase 1 study (AURA1, first-line or later) (see section 5.1). Most adverse reactions were Grade 1or 2 in severity. The most commonly reported adverse drug reactions (ADRs) were diarrhoea (46%),rash (45%), paronychia (33%), dry skin (31%), and stomatitis (23%). Grade 3 and Grade 4 adversereactions across the studies were 11% and 0.2%, respectively. In patients treated with TAGRISSO80 mg once daily, dose reductions due to adverse reactions occurred in 3.4% of the patients.

Discontinuation due to adverse reactions was 5.5%.

The safety of TAGRISSO given in combination with pemetrexed and platinum-based chemotherapy isbased on data in 276 patients with EGFR mutation-positive NSCLC and was consistent with

TAGRISSO monotherapy and known safety profiles of pemetrexed and platinum-basedchemotherapy. The most commonly reported ADRs when TAGRISSO was given in combination withpemetrexed and platinum-based chemotherapy were rash (49%), diarrhoea (43%), decreased appetite(31%), stomatitis (31%), paronychia (27%) and dry skin (24%). When TAGRISSO is administered ascombination therapy, refer to the Summary of Product Characteristics for the respective combinationtherapy components prior to initiation of treatment.

Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroidtreatment, or any evidence of clinically active ILD were excluded from clinical studies. Patients withclinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram(ECG) (e.g. QTc interval greater than 470 msec) were excluded from these studies. Patients wereevaluated for LVEF at screening and every 12 weeks thereafter.

Adverse reactions have been assigned to the frequency categories in Table 2 where possible based onthe incidence of comparable adverse event reports in a pooled dataset from the 1956 EGFRmutation-positive NSCLC patients who received TAGRISSO monotherapy at a dose of 80 mg daily inthe ADAURA, FLAURA, FLAURA2, LAURA, AURA3, AURAex, AURA 2 and AURA1 studiesand in 276 patients treated with TAGRISSO in combination with pemetrexed and platinum-basedchemotherapy in the FLAURA2 study.

Adverse reactions are listed according to system organ class (SOC) in MedDRA. Within each systemorgan class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.

Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness. In addition, the corresponding frequency category for each adverse reaction is based onthe CIOMS III convention and is defined as: very common (≥1/10); common (≥1/100 to <1/10);uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known(cannot be estimated from available data).

Table 2. Adverse reactions reported in ADAURA, LAURA, FLAURA, FLAURA2 and AURAstudies

MedDRA SOC a TAGRISSO with pemetrexed and

TAGRISSOand MedDRA platinum-based chemotherapybterm CIOMS descriptor/ Frequency of CIOMS descriptor/ Frequency ofoverall frequency CTCAE grade overall frequency (all CTCAE(all CTCAE grades)c 3 or higherc CTCAE grades)c grade 3 orhigherc

Aplastic anaemia Rare (0.05%) 0.05% 0% 0%

Thrombocytopenia Common (7%) 0.6% Very common (18.5%) 6.9%

Neutropenia Common (6%) 0.9% Very common (24.6%) 13.4%

Leukopenia Common (5%) 0.4% Very common (12.7%) 2.9%

Lymphopenia Common (1.6%) 0.3% Common (2.5%) 1.1%

Decreased appetite Very common (19%) 1.1% Very common (31%) 2.9%

Keratitisd Uncommon (0.6%) 0.05% Uncommon (0.7%) 0%

Cardiac failure Uncommon (0.5%) 0.2% Common (1.8%) 1.1%e

MedDRA SOC a TAGRISSO with pemetrexed and

TAGRISSOand MedDRA platinum-based chemotherapybterm CIOMS descriptor/ Frequency of CIOMS descriptor/ Frequency ofoverall frequency CTCAE grade overall frequency (all CTCAE(all CTCAE grades)c 3 or higherc CTCAE grades)c grade 3 orhigherc

Epistaxis Common (6%) 0% Common (7%) 0.4%

Interstitial lung Common (4.3%)f 1.4%g Common (3.3%)h 0.7%idisease

Radiation Common (4%) 0.2% 0% 0%

Pneumonitisj

Diarrhoea Very common (46%) 1.5% Very common (43%) 2.9%

Stomatitisk Very common (23%) 0.4% Very common (31%) 0.4%

Rashl Very common (45%) 0.8% Very common (49%) 2.5%

Paronychiam Very common (33%) 0.4% Very common (27%) 0.7%

Dry skinn Very common (31%) 0.2% Very common (24%) 0%

Prurituso Very common (17%) 0.05% Common (8%) 0%

Alopecia Common (5%) 0% Common (9%) 0%

Palmar-plantar Common (1.9%) 0% Common (5%) 0%erythrodysaesthesiasyndrome

Urticaria Common (1.9%) 0.1% Common (1.4%) 0.4%

Skin Uncommon (0.9%) 0% Common (2.5%) 0%hyperpigmentationp

Erythema Uncommon (0.3%) 0% Common (1.4%) 0.7%multiformeq

Cutaneous Uncommon (0.2%) 0% 0%vasculitisr

Stevens-Johnson Rare (0.02%) 0% 0%syndromes

Toxic Epidermal Not known 0% 0%

Necrolysist

Left ventricular Common (4.1%) Common (8.0%)ejection fractiondecreasedu,v

Blood creatine Common (2%) 0.4% Common (3.3%) 1.1%phosphokinaseincreased

QTc interval Common (1.1%) Common (1.8%)prolongationw

Investigations (Findings based on test results presented as CTCAE grade shifts)

Leukocytes Very common (65%) 1.9% Very common (88%) 20%decreasedu

Lymphocytes Very common (64%) 8% Very common (78%) 16%decreasedu

Platelet count Very common (53%) 1.3% Very common (85%) 16%decreasedu

Neutrophils Very common (36%) 4.0% Very common (85%) 36%decreasedu

MedDRA SOC a TAGRISSO with pemetrexed and

TAGRISSOand MedDRA platinum-based chemotherapybterm CIOMS descriptor/ Frequency of CIOMS descriptor/ Frequency ofoverall frequency CTCAE grade overall frequency (all CTCAE(all CTCAE grades)c 3 or higherc CTCAE grades)c grade 3 orhigherc

Blood creatinine Common (5.6%) 0.05% Very common (22%) 0.4%increased

Myositis Uncommon (0.2%) 0% 0% 0%a Data is pooled from ADAURA, FLAURA, FLAURA2 (monotherapy arm), LAURA and AURA (AURA3,

AURAex, AURA 2 and AURA1) studies; only events for patients receiving at least one dose of TAGRISSOas their randomised treatment are summarised.b Data is from the combination arm of the FLAURA2 study; only events for the patients receiving at least onedose of study treatment (TAGRISSO, pemetrexed, cisplatin or carboplatin) as their randomised treatment aresummarised. The median duration of study treatment was 22.3 months for patients in the TAGRISSO withpemetrexed and platinum-based chemotherapy arm.c National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.d Includes: corneal epithelium defect, corneal erosion, keratitis, punctate keratitis.e Two CTCAE Grade 5 events (fatal) were reported.f Includes: interstitial lung disease (1.8%), pneumonitis (2.2%), pulmonary fibrosis (0.2%), organisingpneumonia (0.1%).g Eight CTCAE Grade 5 events (fatal) were reported.h Includes: interstitial lung disease (1.8%), pneumonitis (1.1%), organising pneumonia (0.4%).i One CTCAE Grade 5 event (fatal) was reported.j Includes: radiation fibrosis-lung (0.05%).k Includes: mouth ulceration, stomatitis.l Includes: acne, dermatitis, dermatitis acneiform, drug eruption, erythema, folliculitis, pustule, rash, rasherythematous, rash follicular, rash macular, rash maculo-papular, rash papular, rash pustular, rash pruritic,rash vesicular, skin erosion.m Includes: nail bed disorder, nail bed infection, nail bed inflammation, nail discolouration, nail disorder, naildystrophy, nail infection, nail pigmentation, nail ridging, nail toxicity, onychalgia, onychoclasis, onycholysis,onychomadesis, onychomalacia, paronychia.n Includes: dry skin, eczema, skin fissures, xeroderma, xerosis.o Includes: eyelid pruritus, pruritus.p Cases of erythema dyschromicum perstans have been reported in the post-marketing setting.q Six of the 1956 patients in the ADAURA, AURA, FLAURA, FLAURA2 (monotherapy arm), LAURA and

AURA studies reported erythema multiforme. Post-marketing reports of erythema multiforme have also beenreceived, including 7 reports from a post-marketing surveillance study (N=3578).r Estimated frequency. The upper limit of the 95% CI for the point estimate is 3/1956 (0.4%).s One event was reported in a post-marketing study, and the frequency has been derived from the ADAURA,

FLAURA, FLAURA2 (monotherapy arm), LAURA and AURA studies and the post-marketing study(N=5534).t Reported during post-marketing use.u Represents the incidence of laboratory findings, not of reported adverse events.v Represents decreases greater than or equal to 10 percentage points and a drop to less than 50%.w Represents the incidence of patients who had a QTcF prolongation >500 msec.

Interstitial lung disease (ILD)

In the ADAURA, FLAURA, FLAURA2 (monotherapy arm), AURA and LAURA studies, ILD or

ILD-like adverse reactions were reported in 4.3% of the 1956 patients. Eight fatal cases were reported.

No fatal cases were reported in the adjuvant setting. The incidence of ILD was 10.4% in patients of

Japanese ethnicity, 2.8% in patients of non-Japanese Asian ethnicity and 3.2% in non-Asian patients.

The median time from first dose to onset of ILD or ILD-like adverse reactions was 85 days (seesection 4.4).

ILD or ILD-like adverse reactions were reported in 7.7% and were fatal in 0.7% (n=1) of the 143patients who received TAGRISSO following definitive platinum-based chemoradiation therapy in

LAURA. The incidence of ILD was 6.6% in patients of non-Japanese Asian ethnicity and 17.2% innon-Asian patients; no patients of Japanese ethnicity had an event of ILD. The median time from firstdose to onset of ILD or ILD-like adverse reactions was 1.9 months. The median time from last dose ofradiotherapy to onset of ILD or ILD-like adverse reactions was 3.0 months.

ILD or ILD-like adverse reactions were reported in 3.3% and were fatal in 0.4% (n=1) of the 276patients who received TAGRISSO in combination with pemetrexed and platinum-based chemotherapyin FLAURA2. The incidence of ILD was 14.9% in patients of Japanese ethnicity and 1.7% in non-

Asian patients; no patients of non-Japanese Asian ethnicity had an event of ILD in the FLAURA2combination arm. The median time from first dose to onset of ILD or ILD-like adverse reactions was161 days.

Radiation pneumonitis

In the LAURA study, following definitive platinum-based chemoradiation therapy, radiationpneumonitis was reported in 48% of the 143 patients who received TAGRISSO and 38% of the73 patients who received placebo. Three (2.1%) patients had Grade 3 events, all in the TAGRISSOarm, and no Grade 4 or Grade 5 events were reported in either arm. The median time from first dose toonset of radiation pneumonitis was 1.7 months in the TAGRISSO arm and 1.8 months in the placeboarm. The median time from last dose of radiotherapy to onset of radiation pneumonitis was 2.5 monthsin the TAGRISSO arm and 2.6 months in the placebo arm.

QTc interval prolongation

Of the 1956 patients in ADAURA, FLAURA, FLAURA2, LAURA and AURA studies treated with

TAGRISSO monotherapy 80 mg, 1.1% of patients (n=21) were found to have a QTc greater than 500msec, and 4% of patients (n=79) had an increase from baseline QTc greater than 60 msec. Apharmacokinetic/ pharmacodynamic analysis with TAGRISSO predicted a concentration-dependentincrease in QTc interval prolongation. No QTc-related arrhythmias were reported in the ADAURA,

LAURA, FLAURA, FLAURA2 or AURA studies (see sections 4.4 and 5.1). In patients who received

TAGRISSO in combination with pemetrexed and platinum-based chemotherapy, the proportion ofpatients who experienced a QTc interval prolongation of greater than 500 msec with a greater than 60msec increase from baseline was low and was similar with monotherapy (1.8% versus 1.5%).

In the ADAURA, FLAURA, FLAURA2, LAURA and AURA studies (TAGRISSO monotherapy;

N=1956), diarrhoea was reported in 46% of patients of which 36% were Grade 1 events, 8. 1% Grade2 and 1.5% were Grade 3; no Grade 4 or 5 events were reported. Dose reduction was required in 0.6%of patients and dose interruption in 1.9%. Four events (0.2%) led to discontinuation. In ADAURA,

FLAURA, FLAURA2 (monotherapy arm) and AURA3 the median time to onset was 22 days, 19days, 22 days and 22 days, respectively, and the median duration of the Grade 2 events was 11 days,19 days, 17 days and 6 days, respectively. In patients who received TAGRISSO in combination withpemetrexed and platinum-based chemotherapy, diarrhoea was reported in 43% of patients versus 41%of patients in monotherapy, most of these diarrhoea events were Grade 1 and Grade 2 events.

Haematological events

Early reductions in the median laboratory counts of leukocytes, lymphocytes, neutrophils and plateletshave been observed in patients treated with TAGRISSO, which stabilised over time and then remainedabove the lower limit of normal. Adverse events of leukopenia, lymphopenia, neutropenia andthrombocytopenia have been reported, most of which were mild or moderate in severity and did notlead to dose interruptions. Rare cases of aplastic anaemia, including fatal events, have been reported inassociation with TAGRISSO treatment. TAGRISSO should be discontinued in patients withconfirmed aplastic anaemia (see section 4.2 and 4.4).

In ADAURA, FLAURA, FLAURA2, LAURA and AURA3 (TAGRISSO monotherapy; N=1956),43% of patients were 65 years of age and older, and 11% were 75 years of age and older. Comparedwith younger patients (<65), more patients ≥65 years old had reported adverse reactions that led tostudy dose modifications (interruptions or reductions) (18% versus 13%). The types of adverse eventsreported were similar regardless of age. Older patients reported more Grade 3 or higher adversereactions compared to younger patients (14% versus 9%). No overall differences in efficacy wereobserved between older and younger patients. A consistent pattern in safety and efficacy results wasobserved in the analysis of AURA Phase 2 studies. Of the 276 patients treated with TAGRISSO incombination with pemetrexed and platinum-based chemotherapy, 104 patients were ≥65 years and 23patients were ≥75 years of age. Older patients (≥65 years) reported similar Grade 3 or higher adversereactions compared to <65 years old patients (36% versus 36%) respectively. Dose modification foradverse reactions were reported in a higher proportion of patients ≥65 years as compared to <65 years(34% vs 20%).

Low body weight

Patients receiving TAGRISSO monotherapy (80 mg; N=1956) with low body weight (<50 kg)reported higher frequencies of Grade ≥3 adverse reactions (20% versus 10%) and QTc prolongation(12% versus 6%) than patients with higher body weight (≥50 kg). Patients who received TAGRISSOin combination with pemetrexed and platinum-based chemotherapy with low body weight (<50 kg)reported similar frequencies of Grade ≥3 adverse reactions (32% versus 37%) when compared topatients with higher body weight (≥50 kg). In contrast, dry skin (34% versus 22%) and stomatitis(40% versus 30%) were reported at higher frequencies in patients with low body weight (<50 kg)versus higher body weight (≥50 kg).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In TAGRISSO clinical studies, a limited number of patients were treated with daily doses of up to240 mg without dose limiting toxicities. In these studies, patients who were treated with TAGRISSOdaily doses of 160 mg and 240 mg experienced an increase in the frequency and severity of a numberof typical EGFR TKI-induced AEs (primarily diarrhoea and skin rash) compared to the 80 mg dose.

There is limited experience with accidental overdoses in humans. All cases were isolated incidents ofpatients taking an additional daily dose of TAGRISSO in error, without any resulting clinicalconsequences.

There is no specific treatment in the event of TAGRISSO overdose. In case of suspected overdose,

TAGRISSO should be withheld and symptomatic treatment initiated.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors. ATC code: L01EB04.

Osimertinib is a Tyrosine Kinase Inhibitor (TKI). It is an irreversible inhibitor of EGFRs harboringsensitising-mutations (EGFRm) and TKI-resistance mutation T790M.

In vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against

EGFR across a range of all clinically relevant EGFR sensitising-mutant and T790M mutant NSCLCcell lines (apparent IC50s from 6 nM to 54 nM against phospho-EGFR). This leads to inhibition of cellgrowth, while showing significantly less activity against EGFR in wild-type cell lines (apparent IC50sfrom 480 nM to 1.8 μM against phospho-EGFR). In vivo oral administration of osimertinib lead totumour shrinkage in both EGFRm and T790M NSCLC xenograft and transgenic mouse lung tumourmodels.

The QTc interval prolongation potential of TAGRISSO was assessed in 210 patients who receivedosimertinib 80 mg daily in AURA2. Serial ECGs were collected following a single dose and atsteady-state to evaluate the effect of osimertinib on QTc intervals. Apharmacokinetic/pharmacodynamic analysis predicted a drug-related QTc interval prolongation at80 mg of 14 msec with an upper bound of 16 msec (90% CI).

Adjuvant treatment of EGFR mutation-positive NSCLC, with or without prior adjuvant chemotherapy- ADAURA

The efficacy and safety of TAGRISSO for the adjuvant treatment of patients with EGFR mutation-positive (Ex19del or L858R) NSCLC who have had complete tumour resection with or without prioradjuvant chemotherapy was demonstrated in a randomised, double-blind, placebo-controlled study(ADAURA).

Eligible patients with resectable tumors stage IB-IIIA (according to American Joint Commission on

Cancer [AJCC] 7th edition) were required to have EGFR mutations (Ex19del or L858R), identified bythe cobas EGFR Mutation Test performed prospectively using biopsy or surgical specimen in a centrallaboratory.

Patients were randomised 1:1 to receive TAGRISSO (n=339, 80 mg orally once daily) or placebo(n=343) following recovery from surgery and standard adjuvant chemotherapy where given. Patientsnot receiving adjuvant chemotherapy were randomised within 10 weeks and patients receivingadjuvant chemotherapy within 26 weeks following surgery. Randomisation was stratified by EGFRmutation type (Ex19del or L858R), ethnicity (Asian or non-Asian) and staging based on pathologicaltumor-node-metastasis (pTNM) (IB or II or IIIA) according to AJCC 7th edition. Treatment was givenuntil disease recurrence, unacceptable toxicity, or for 3 years.

The major efficacy outcome measure was disease-free survival (DFS) by investigator assessment inthe stage II-IIIA population. DFS by investigator assessment in the stage IB-IIIA population (overallpopulation) was an additional efficacy outcome measure. Other additional efficacy outcome measuresincluded DFS rate, overall survival (OS), OS rate, and time to deterioration in health-related quality oflife (HRQoL) SF-36.

The baseline demographic and disease characteristics of the overall population were: median age63 years (range 30-86 years), ≥75 years old (11%), female (70%), Asian (64%), never smokers (72%),

World Health Organization (WHO) performance status of 0 (64%) or 1 (36%), stage IB (31%), stage

II (34%), and IIIA (35%). With regards to EGFR mutation status, 55% were exon 19 deletions and45% were exon 21 L858R substitution mutations; 9 patients (1%) also had a concurrent de novo

T790M mutation. The majority (60%) of patients received adjuvant chemotherapy prior torandomisation (26% IB; 71% IIA; 73% IIB; 80% IIIA). At the time of the DFS analysis, 205 (61%)patients were still on active treatment; of the 73 (11%) patients who had the opportunity to completethe 3-year treatment period, 40 (12%) were in the osimertinib arm and 33 (10%) in the placebo arm.

There were 37 patients who had disease recurrence on TAGRISSO. The most commonly reported sitesof recurrence were: lung (19 patients); lymph nodes (10 patients) and central nervous system (CNS)(5 patients). There were 157 patients who had disease recurrence on placebo. The most commonlyreported sites were: lung (61 patients); lymph nodes (48 patients) and CNS (34 patients).

ADAURA demonstrated a statistically significant reduction in the risk of disease recurrence or deathfor patients treated with TAGRISSO compared to patients treated with placebo in the stage II-IIIApopulation. Similar results were observed in the stage IB-IIIA population.

Efficacy results from ADAURA by investigator assessment are summarised in Table 3.

Table 3. Efficacy results from ADAURA by investigator assessment

Stage II-IIIA population Stage IB-IIIA population

Efficacy parameter TAGRISSO Placebo TAGRISSO Placebo(N=233) (N=237) (N=339) (N=343)

Disease-free survival

Number of events (%) 26 (11) 130 (55) 37 (11) 159 (46)

Recurrent disease (%) 26 (11) 129 (54) 37 (11) 157 (46)

Deaths (%) 0 1 (0.4) 0 2 (0.6)

Median DFS, months

NC (38.8, NC) 19.6 (16.6, 24.5) NC (NC, NC) 27.5 (22.0, 35.0)(95% CI)

HR (99.06% CI);0.17 (0.11, 0.26); <0.0001a 0.20 (0.14, 0.30); <0.0001b

P-value

DFS rate at 12 months97 (94, 99) 61 (54, 67) 97 (95, 99) 69 (63, 73)(%) (95% CI)

DFS rate at 24 months90 (84, 93) 44 (37, 51) 89 (85, 92) 52 (46, 58)(%) (95% CI)

DFS rate at 36 months78 (65, 87) 28 (19, 38) 79 (69, 86) 40 (32, 48)(%) (95% CI)c,d

HR=Hazard Ratio; CI=Confidence Interval; NC=Not Calculable

DFS results based on investigator assessment.

A HR <1 favours TAGRISSO.

Median follow-up time for DFS was 22.1 months for patients receiving TAGRISSO, 14.9 months for patients receivingplacebo (stage II-IIIA population) and 16.6 months for patients receiving placebo (stage IB-IIIA population).

DFS results are from the primary analysis (17 January 2020).

a Adjusted for an interim analysis (33% maturity) a p-value <0.0094 was required to achieve statistical significance.b Adjusted for an interim analysis (29% maturity) a p-value <0.0088 was required to achieve statistical significance.c The number of patients at risk at 36 months was 18 patients in the TAGRISSO arm and 9 patients in the placebo arm (stage

II-IIIA population).d The number of patients at risk at 36 months was 27 patients in the TAGRISSO arm and 20 patients in the placebo arm(stage IB-IIIA population).

The final analysis of OS (data cut-off [DCO]: 27 January 2023) demonstrated a statistically significantimprovement in OS for patients treated with TAGRISSO compared to placebo for both the stage II-

IIIA population (100 OS events [21% maturity]; HR=0.49; 95.03% CI: 0.33, 0.73; p-value=0.0004)and the overall population (IB-IIIA; 124 OS events [18% maturity]; HR=0.49; 95.03% CI: 0.34, 0.70;p-value <0.0001). For both populations, the median OS was not reached in either treatment arm andthe 95% CIs were not calculable. The median follow-up time for OS in all patients was 59.9 months(stage II-IIIA population) and 60.4 months (stage IB-IIIA population) in the TAGRISSO arm and56.2 months (stage II-IIIA population) and 59.4 months (stage IB-IIIA population) in the placebo arm.

Figure 1. Kaplan-Meier curve of disease-free survival in stage II-IIIA patients by investigatorassessment

TAGRISSO (N=233)

Median NC

Placebo (N=237)

Median 19.6 months

Hazard Ratio = 0.1799.06% CI (0.11,0.26)

P-value <0.0001

TAGRISSO

Placebo

Number at risk Time from randomisation (months)

TAGRISSO

Placebo+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

NC = Not Calculable.

Probability of Disease-Free Survival

Figure 2. Kaplan-Meier curve of disease-free survival in stage IB-IIIA (overall population)patients by investigator assessment

TAGRISSO (N=339)

Median NC

Placebo (N=343)

Median 27.5 months

Hazard Ratio = 0.2099.12% CI (0.14, 0.30)

P-value <0.0001

Number at risk

TAGRISSO TAGRISSO

Placebo Placebo

Time from randomisation (months)+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

NC = Not Calculable.

The DFS benefit of TAGRISSO compared to placebo was consistent across all predefined subgroupsanalysed, including ethnicity, age, gender, and EGFR mutation type (Ex19Del or L858R).

Figure 3. Kaplan-Meier curve of overall survival in stage II-IIIA patients

Hazard Ratio = 0.4995.03% CI (0.33, 0.73)

P-value 0.0004

TAGRISSO

Placebo

Time from randomisation (months)

Number at risk

TAGRISSO

Placebo+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

Probability of Overall Survival Probability of Disease-Free Survival

Figure 4. Kaplan-Meier curve of overall survival in stage IB-IIIA (overall population) patients

Hazard Ratio = 0.4995.03% CI (0.34, 0.70)

P-value <0.0001

TAGRISSO

Placebo

Time from randomisation (months)

Number at risk

TAGRISSO

Placebo+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

An exploratory analysis of CNS DFS (time to CNS recurrence or death) for patients on TAGRISSOcompared to patients on placebo showed a HR of 0.18 (95% CI: 0.10, 0.33; p<0.0001) for the overallpopulation (stage IB-IIIA).

Patient-reported outcomes

Health-related quality of life (HRQL) in ADAURA was assessed using the Short Form (36) Health

Survey version 2 (SF-36v2) questionnaire. SF-36v2 was administered at 12 weeks, 24 weeks and thenevery 24 weeks relative to randomisation until treatment completion or discontinuation. Overall,

HRQL was maintained in both arms up to 30 months, with at least 70% of patients in the stage II-IIIApopulation not experiencing a clinically meaningful deterioration in the physical component of the

SF-36 or death (70% vs 76% for TAGRISSO vs placebo), or in the mental component of the SF-36 ordeath (70% vs 71% for TAGRISSO vs placebo).

Locally advanced, unresectable EGFR mutation-positive NSCLC - LAURA

The efficacy and safety of TAGRISSO for the treatment of patients with EGFR mutation-positive,locally advanced, unresectable NSCLC, who had not progressed during or following definitiveplatinum-based chemoradiation therapy, were evaluated in a randomised, double-blind,placebo-controlled study (LAURA). Patients were to receive concurrent chemoradiation therapy(CCRT) or sequential chemoradiation therapy (SCRT) regimens, where at least 2 cycles or 5 weeklydoses of platinum-based chemotherapy and a total dose of radiation of 60 Gy ±10% (54 Gy to 66 Gy),were to be completed ≤6 weeks prior to randomisation. Patient tumour tissue samples were required tohave an EGFR exon 19 deletion or exon 21 L858R mutation, as identified by central or local testingusing a certified/approved test.

Probability of Overall Survival

Patients were randomised (2:1) to receive either TAGRISSO 80 mg orally once daily (n=143) orplacebo (n=73). Randomisation was stratified by prior chemoradiation strategy (CCRT vs SCRT),tumour staging prior to chemoradiation (IIIA vs IIIB/IIIC), and by the China cohort. Patientscontinued to receive study treatment until intolerance to therapy or confirmed disease progression.

Cross-over from placebo to TAGRISSO was permitted upon progressive disease.

The primary efficacy endpoint was progression-free survival (PFS) as assessed by blinded independentcentral review (BICR). Additional efficacy endpoints included OS and CNS PFS as assessed byneuroradiologist BICR.

The baseline demographic and disease characteristics of the overall study population were: median age63 years (range 36-84 years), ≥75 years old (13%), female (61%), Asian (82%), White (14%), neversmokers (70%). Baseline WHO performance status was 0 (51%) or 1 (49%); 35% of patients had stage

IIIA, 49% of patients had stage IIIB and 16% of patients had stage IIIC NSCLC. With regard to EGFRmutation status, 54% were exon 19 deletions and 45% were exon 21 L858R mutations. Prior torandomisation, 89% of patients received CCRT and 11% of patients received SCRT. All patientsreceived platinum-based chemotherapy (55% carboplatin-based chemotherapy and 44%cisplatin-based chemotherapy). The median total dose of radiation was 60 Gy for patients in botharms.

Treatment with TAGRISSO following platinum-based chemoradiation therapy resulted in astatistically significant improvement in PFS compared to placebo (56% maturity; HR=0.16; 95% CI:

0.10, 0.24; P<0.001, median 39.1 months and 5.6 months, respectively).

Per protocol, all patients underwent baseline magnetic resonance imaging (MRI) brain scans and allbut one patient had scheduled on-treatment MRI brain scans. A lower proportion of patients had new

CNS lesions by neuroradiologist review in the TAGRISSO arm compared to the placebo arm (17/143[12%] vs. 26/73 [36%], respectively).

At the time of the interim analysis of OS (DCO: 05 January 2024), statistical significance was notreached. Fifty out of 62 patients (80.6%) in placebo arm were treated with TAGRISSO post-BICRconfirmed disease progression.

Efficacy results from LAURA are summarised in Table 4, and the Kaplan-Meier curve for PFS isshown in Figure 5.

Table 4. Efficacy results from LAURA

TAGRISSO Placebo

Efficacy Parameter(N=143) (N=73)

Progression-Free Survivala

Number (%) of events 57 (40) 63 (86)

Median PFS, months (95% CI) 39.1 (31.5, NC) 5.6 (3.7, 7.4)

HR (95% CI); P-value 0.16 (0.10, 0.24); P<0.001

Overall Survival

Number (%) of deaths 28 (20) 15 (21)

Median OS, months (95% CI) 54.0 (46.5, NC) NC (42.1, NC)

TAGRISSO Placebo

Efficacy Parameter(N=143) (N=73)

HR (95% CI); P-value 0.81 (0.42, 1.56); P=0.530a

HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable

PFS results as assessed by BICR.

Median follow-up time for PFS in all patients was 22.0 months in the TAGRISSO arm and 5.6 months in theplacebo arm.a Adjusted for an interim analysis (20% maturity) a p-value <0.000036 was required to achieve statisticalsignificance.

Figure 5. Kaplan-Meier Curves of Progression-Free Survival as assessed by BICR in LAURA

TAGRISSO (N=143)

Median 39.1 months

Placebo (N=73)

Median 5.6 months

Hazard Ratio=0.1695% CI (0.10, 0.24)

P-value <0.001

TAGRISSO

Placebo

Time from randomisation (months)

Number at risk

TAGRISSO

Placebo+ Censored patients.

The values at the base of the figure indicate number of patients at risk.

Previously untreated EGFR mutation-positive locally advanced or metastatic NSCLC

FLAURA- Monotherapy

The efficacy and safety of TAGRISSO for the treatment of patients with EGFR mutation-positivelocally advanced, not amenable to curative surgery or radiotherapy, or metastatic NSCLC, who hadnot received previous systemic treatment for advanced disease, was demonstrated in a randomised,double-blind, active-controlled study (FLAURA). Patient tumour tissue samples were required to haveone of the two common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19delor L858R), as identified by local or central testing.

Patients were randomised 1:1 to receive either TAGRISSO (n=279, 80 mg orally once daily) or EGFR

TKI comparator (n=277; gefitinib 250 mg orally once daily or erlotinib 150 mg orally once daily).

Randomisation was stratified by EGFR mutation type (Ex19del or L858R) and ethnicity (Asian ornon-Asian). Patients received study therapy until intolerance to therapy, or the investigator determinedthat the patient was no longer experiencing clinical benefit. For patients receiving EGFR TKI

Probability of Progression-Free Survivalcomparator, post-progression crossover to open-label TAGRISSO was permitted provided tumoursamples tested positive for the T790M mutation. The primary efficacy endpoint was PFS as assessedby investigator.

The baseline demographic and disease characteristics of the overall study population were: median age64 years (range 26-93 years), ≥75 years old (14%), female (63%), White (36%), Asian (62%), neversmokers (64%), WHO performance status of 0 or 1 (100%), metastatic bone disease (36%), extra-thoracic visceral metastases (35%), CNS metastases (21%, identified by CNS lesion site at baseline,medical history, and/or prior surgery, and/or prior radiotherapy to CNS metastases).

TAGRISSO demonstrated a clinically meaningful and statistically significant improvement in PFScompared to EGFR TKI comparator (median 18.9 months and 10.2 months, respectively, HR=0.46,95% CI: 0.37, 0.57; P<0.0001). Efficacy results from FLAURA by investigator assessment aresummarised in Table 5, and the Kaplan-Meier curve for PFS is shown in Figure 6. The final analysisof OS, (58% maturity) demonstrated a statistically significant improvement with an HR of 0.799(95.05% CI: 0.641, 0.997) and a clinically meaningful longer median survival time in patientsrandomised to TAGRISSO compared to EGFR TKI comparator (Table 5 and Figure 7). A greaterproportion of patients treated with TAGRISSO were alive at 12, 18, 24 and 36 months (89%, 81%,74% and 54% respectively) compared to patients treated with EGFR TKI comparator (83%, 71%, 59%and 44% respectively). Analysis of post-progression endpoints demonstrated that the PFS benefit waspreserved through subsequent lines of therapy.

Table 5. Efficacy results from FLAURA by investigator assessment

Efficacy parameter TAGRISSO EGFR TKI comparator(N=279) (gefitinib or erlotinib)(N=277)

Progression-free survival

Number of events (62% maturity) 136 (49) 206 (74)

Median PFS, months (95% CI) 18.9 (15.2, 21.4) 10.2 (9.6, 11.1)

HR (95% CI); P-value 0.46 (0.37, 0.57); P<0.0001

Overall survival

Number of deaths, (58% maturity) 155 (56) 166 (60)

Median OS, months (95% CI) 38.6 (34.5, 41.8) 31.8 (26.6, 36.0)

HR (95.05% CI); P-value 0.799 (0.641, 0.997); P=0.0462a

Objective response rate*b

Number of responses (n), Response Rate 223 210(95% CI) 80% (75, 85) 76% (70, 81)

Odds ratio (95% CI); P-value 1.3 (0.9, 1.9); P=0.2421

Duration of response (DoR)*

Median DoR, months (95% CI) 17.2 (13.8, 22.0) 8.5 (7.3, 9.8)

Second PFS after start of first subsequent therapy (PFS2)

Number of patients with second73 (26) 106 (38)progression (%)

Median PFS2, months (95% CI) NC (23.7, NC) 20.0 (18.0, NC)

HR (95% CI); P-value 0.58 (0.44, 0.78); P=0.0004

Time from randomisation to first subsequent treatment or death (TFST)

Number of patients who had first115 (41) 175 (63)subsequent treatment or died (%)

Median TFST, months (95% CI) 23.5 (22.0, NC) 13.8 (12.3, 15.7)

HR (95% CI); P-value 0.51 (0.40, 0.64); P<0.0001

Time from randomisation to second subsequent treatment or death (TSST)

Number of patients who had second75 (27) 110 (40)subsequent treatment or died (%)

Median TSST, months (95% CI) NC (NC, NC) 25.9 (20.0, NC)

HR (95% CI); P-value 0.60 (0.45, 0.80); P=0.0005

HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable

PFS, ORR, DoR and PFS2 results based on RECIST investigator assessment.

*Based on unconfirmed response.

Median follow-up time was 15.0 months for patients receiving TAGRISSO and 9.7 months for patients receiving

EGFR TKI comparator.

Median survival follow-up time was 35.8 months for patients receiving TAGRISSO and 27.0 months for patientsreceiving EGFR TKI comparator.

PFS, ORR, DoR, PFS2, TFST and TSST results are from DCO 12 June 2017. OS results are from DCO 25 June2019.

A HR <1 favours TAGRISSO, an Odds ratio of >1 favours TAGRISSO.a Adjusted for an interim analysis (25% maturity) a p-value <0.0495 was required to achieve statisticalsignificance.b ORR results by BICR were consistent with those reported via investigator assessment; ORR by BICRassessment was 78% (95% CI: 73, 83) on TAGRISSO and 70% (95% CI: 65, 76) on EGFR TKI comparator.

Figure 6. Kaplan-Meier curves of progression-free survival as assessed by investigator in

FLAURA

TAGRISSO (N=279)

Median 18.9 months

SoC (N=277)

Median 10.2 months

Hazard Ratio = 0.4695% CI (0.37, 0.57)

P-value <0.0001

TAGRISSO

SoC

Time from randomisation (months)

Number at risk

TAGRISSO

SoC+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

Figure 7. Kaplan-Meier curves of overall survival in FLAURA

TAGRISSO (N=279)

Median 38.6 months

SoC (N=277)

Median 31.8 months

Hazard Ratio = 0.79995.05% CI (0.641, 0.997)

P-value 0.0462

TAGRISSO

SoC

Number at risk Time from randomisation (months)

TAGRISSO

SoC+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

Probability of Progression-Free Survival

Probability of Overall Survival

The PFS benefit of TAGRISSO compared to EGFR TKI comparator was consistent across allpredefined subgroups analysed, including ethnicity, age, gender, smoking history, CNS metastasesstatus at study entry and EGFR mutation type (Exon 19 deletion or L858R).

CNS metastases efficacy data in FLAURA study

Patients with CNS metastases not requiring steroids and with stable neurologic status for at least twoweeks after completion of the definitive therapy and steroids were eligible to be randomised in the

FLAURA study. Of 556 patients, 200 patients had available baseline brain scans. A Blinded

Independent Central Review (BICR) assessment of these scans resulted in a subgroup of 128/556(23%) patients with CNS metastases and these data are summarised in Table 6. CNS efficacy by

RECIST v1.1 in FLAURA demonstrated a statistically significant improvement in CNS PFS(HR=0.48, 95% CI: 0.26, 0.86; P=0.014).

Table 6. CNS efficacy by BICR in patients with CNS metastases on a baseline brain scan in

FLAURA

Efficacy parameter TAGRISSO EGFR TKI comparator

N=61 (gefitinib or erlotinib)

N=67

CNS progression-free survival a

Number of events (%) 18 (30) 30 (45)

Median CNS PFS, months (95% CI) NC (16.5, NC) 13.9 (8.3, NC)

HR (95% CI); P-value 0.48 (0.26, 0.86); P=0.014

CNS progression free and alive at 687 (74, 94) 71 (57, 81)months (%) (95% CI)

CNS progression free and alive at77 (62, 86) 56 (42, 68)12 months (%) (95% CI)

HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable

A HR <1 favours TAGRISSO, an Odds ratio of >1 favours TAGRISSO.a CNS PFS determined by RECIST v1.1by CNS BICR (CNS measurable and non-measurable lesions atbaseline by BICR) n=61 for TAGRISSO and n=67 for EGFR TKI comparator; responses are unconfirmed.

A pre-specified PFS subgroup based on CNS metastases status (identified by CNS lesion site atbaseline, medical history, and/or prior surgery, and/or prior radiotherapy to CNS metastases) at studyentry was performed in FLAURA and is shown in Figure 8. Irrespective of CNS lesion status at studyentry, patients in the TAGRISSO arm demonstrated an efficacy benefit over those in the EGFR TKIcomparator arm and there were fewer patients with new CNS lesions in the TAGRISSO arm comparedto the EGFR TKI comparator arm (TAGRISSO, 11/279 [3.9%] compared to EGFR TKI comparator,34/277 [12.3%]). In the subset of patients without CNS lesions at baseline, there were a lower numberof new CNS lesions in the TAGRISSO arm compared to the EGFR TKI comparator arm (7/226[3.1%] vs. 15/214 [7.0%], respectively).

Figure 8. Overall PFS by investigator assessment by CNS metastases status at study entry,

Kaplan-Meier plot (full analysis set) in FLAURA

CNS Metastases = No CNS Metastases = Yes

TAGRISSO (N=226) TAGRISSO (N=53)

Median 19.1 months Median 15.2 months

SoC (N=214) SoC (N=63)

Median 10.9 months Median 9.6 months

Hazard Ratio = 0.46 Hazard Ratio = 0.4795% CI (0.36, 0.59) 95% CI (0.30, 0.74)

P-value <0.0001 P-value 0.00091. CNS Metastases at Entry = No: TAGRISSO2. CNS Metastases at Entry = No: SoC3. CNS Metastases at Entry = Yes: TAGRISSO4. CNS Metastases at Entry = Yes: SoC

Time from randomisation (months)

Number at risk1.2.

3.

4.

+ Censored patients.

The values at the base of the figure indicate number of subjects at risk.

Patient-reported outcomes

Patient-reported symptoms and HRQL were electronically collected using the EORTC QLQ-C30 andits lung cancer module (EORTC QLQ-LC13). The LC13 was initially administered once a week forthe first 6 weeks, then every 3 weeks before and after progression. The C30 was assessed every 6weeks before and after progression. At baseline, no differences in patient reported symptoms, functionor HRQL were observed between TAGRISSO and EGFR TKI comparator (gefitinib or erlotinib)arms. Compliance over the first 9 months was generally high (≥70%) and similar in both arms.

Key lung cancer symptoms analysis

Data collected from baseline up to month 9 showed similar improvements in TAGRISSO and EGFR

TKI comparator groups for the five pre-specified primary PRO symptoms (cough, dyspnoea, chestpain, fatigue, and appetite loss) with improvement in cough reaching the established clinically relevantcut-off. Up to month 9 there were no clinically meaningful differences in patient-reported symptomsbetween TAGRISSO and EGFR TKI comparator groups (as assessed by a difference of ≥10 points).

HRQL and physical functioning improvement analysis

Both groups reported similar improvements in most functioning domains and global healthstatus/HRQL, indicating that patients’ overall health status improved. Up to month 9, there were noclinically meaningful differences between the TAGRISSO and EGFR TKI comparator groups infunctioning or HRQL.

FLAURA2 - Combination Therapy

Probability of Progression-Free Survival

The efficacy and safety of TAGRISSO in combination with pemetrexed and platinum-basedchemotherapy for the treatment of patients with EGFR mutation-positive locally advanced ormetastatic NSCLC, who had not received previous systemic treatment for advanced disease, wasdemonstrated in a randomised, open-label, active-controlled study (FLAURA2). Patient tumour tissuesamples were required to have one of the two common EGFR mutations known to be associated with

EGFR TKI sensitivity (Ex19del or L858R), as identified by local or central testing.

Patients were randomised (1:1) to one of the following treatment arms:

* TAGRISSO (80 mg) orally once daily with pemetrexed (500 mg/m2) and the investigator’s choiceof cisplatin (75 mg/m2) or carboplatin (AUC5) administered intravenously on Day 1 of every 21-day cycle for 4 cycles, followed by TAGRISSO (80 mg) orally once daily and pemetrexed(500 mg/m2) administered intravenously every 3 weeks (n=279)

* TAGRISSO (80 mg) orally once daily (n=278)

Randomisation was stratified by race (Chinese/Asian, non-Chinese/Asian or non-Asian), WHOperformance status (0 or 1), and method for tissue testing (central or local). Patients received studytherapy until intolerance to therapy, or the investigator determined that the patient was no longerexperiencing clinical benefit.

The primary efficacy endpoint was PFS as assessed by investigator per RECIST 1.1 and the keysecondary efficacy endpoint was OS.

The baseline demographic and disease characteristics of the overall study population were: median age61 years (range 26-85 years), ≥75 years old (8%), female (61%), Asian (64%), White (28%), neversmokers (66%). Baseline WHO performance status was 0 (37%) or 1 (63%); 98.7% hadpredominantly adenocarcinoma histology. Of the patients who had metastatic disease, 49% hadmetastatic bone disease, 53% had extra-thoracic metastases and 20% had liver metastases. Forty-onepercent (41%) of patients had CNS metastases (identified by investigator based on CNS lesion site atbaseline, medical history, and/or prior surgery, and/or prior radiotherapy to CNS metastases). Withregard to tumour EGFR mutation type at randomisation, 60.5% were exon 19 deletions and 38.2%were exon 21 L858R; 0.7% of patients had tumours with both exon 19 deletions and exon 21 L858R.

TAGRISSO in combination with pemetrexed and platinum-based chemotherapy demonstrated astatistically significant improvement in PFS compared to TAGRISSO monotherapy. The PFS benefitwas consistent across all subgroups analysed. At the time of the second interim analysis of OS (DCO08 January 2024), statistical significance was not reached.

Efficacy results from FLAURA2 by investigator assessment are summarised in Table 7, the

Kaplan-Meier curve for PFS is shown in Figure 9 and the Kaplan-Meier curve for OS is shown in

Figure 10.

Table 7. Efficacy results from FLAURA2 by investigator assessment

TAGRISSO withpemetrexed and TAGRISSO

Efficacy parameterplatinum-based (N=278)chemotherapy (N=279)

Progression-Free Survival

Number (%) of events 120 (43) 166 (60)

Median PFS, months (95% CI)a 25.5 (24.7, NC) 16.7 (14.1, 21.3)

HR (95% CI); P-value 0.62 (0.49, 0.79); P<0.0001

TAGRISSO withpemetrexed and TAGRISSO

Efficacy parameterplatinum-based (N=278)chemotherapy (N=279)

Overall Survival

Number (%) of deaths 100 (36) 126 (45)

Median OS, months (95% CI) NC (38.0, NC) 36.7 (33.2, NC)

HR (95% CI); P-value 0.75 (0.57, 0.97); P=0.0280b

HR=Hazard Ratio; CI=Confidence Interval, NC=Not Calculable

PFS based on RECIST investigator assessment.

Median follow-up time for PFS in all patients was 19.5 months in the TAGRISSO with pemetrexed and platinum-basedchemotherapy arm and 16.5 months in the TAGRISSO monotherapy arm.

PFS results are from DCO 03 April 2023 (51% maturity). OS results are from DCO 08 January 2024 (41% maturity).a PFS results by BICR were consistent with those reported via investigator assessment.b Based on the second interim analysis (41% maturity) a p-value <0.000001 was required to achieve statistical significance.

Figure 9. Kaplan-Meier curves of progression-free survival as assessed by investigator in

FLAURA2

TAGRISSO + Chemo (N=279)

Median 25.5 months

TAGRISSO (N=278)

Median 16.7 months

Hazard Ratio = 0.6295% CI (0.49, 0.79)

P-value <0.0001

TAGRISSO + Chemo

TAGRISSO

Time from randomisation (months)

Number at risk

TAGRISSO + Chemo

TAGRISSO+ Censored patients.

Chemo = Pemetrexed and platinum-based chemotherapy.

The values at the base of the figure indicate number of patients at risk.

Probability of Progression-Free Survival

Figure 10. Kaplan-Meier Curves of Overall Survival in FLAURA2

TAGRISSO + Chemo (N=279)

Median NC

TAGRISSO (N=278)

Median 36.7 months

Hazard Ratio = 0.7595% CI (0.57, 0.97)

TAGRISSO + Chemo

TAGRISSO P-value 0.0280

Time from randomisation (months)

Number at risk

TAGRISSO + Chemo

TAGRISSO+ Censored patients.

Chemo = Pemetrexed and platinum-based chemotherapy.

The values at the base of the figure indicate number of patients at risk.

CNS metastases efficacy data in FLAURA2 study

Patients with asymptomatic CNS metastases not requiring steroids and with stable neurologic statusfor at least two weeks after completion of the definitive therapy and steroids were eligible to berandomised in the FLAURA2 study. All patients had available baseline brain scans. A BICRassessment, using modified RECIST, of these scans resulted in a subgroup of 222/557 (40%) patientswith CNS measurable and/or non-measurable lesions (cFAS) and a further subgroup of 78/557 (14%)patients with CNS measurable lesions (cEFR). Based on an exploratory analysis, CNS response ratewas >65% in both treatment arms with a higher complete response rate in the TAGRISSO withpemetrexed and platinum-based chemotherapy arm (59.3% of patients) compared to the TAGRISSOmonotherapy arm (43.3% of patients). Median DoR was not reached in the TAGRISSO withpemetrexed and platinum-based chemotherapy arm and was 26.2 months in the TAGRISSOmonotherapy arm. In the cEFR subgroup, 47.5% of patients in the TAGRISSO with pemetrexed andplatinum-based chemotherapy arm had a CNS complete response compared to 15.8% of patients in the

TAGRISSO monotherapy arm.

Pre-treated T790M-positive NSCLC patients - AURA3

The efficacy and safety of TAGRISSO for the treatment of patients with locally advanced ormetastatic T790M NSCLC whose disease has progressed on or after EGFR TKI therapy, wasdemonstrated in a randomised, open-label, active-controlled Phase 3 study (AURA3). All patientswere required to have EGFR T790M mutation-positive NSCLC identified by the cobas EGFRmutation test performed in a central laboratory prior to randomisation. The T790M mutation statuswas also assessed using ctDNA extracted from a plasma sample taken during screening. The primaryefficacy outcome was PFS as assessed by investigator. Additional efficacy outcome measures included

ORR, DoR and OS as assessed by investigator.

Patients were randomised in a 2:1 (TAGRISSO: platinum-based doublet chemotherapy) ratio toreceive TAGRISSO (n=279) or platinum-based doublet chemotherapy (n=140). Randomisation wasstratified by ethnicity (Asian and non-Asian). Patients in the TAGRISSO arm received TAGRISSO

Probability of Overall Survival80 mg orally once daily until intolerance to therapy, or the investigator determined that the patient wasno longer experiencing clinical benefit. Chemotherapy consisted of pemetrexed 500 mg/m2 withcarboplatin AUC5 or pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 on Day 1 of every 21-day cyclefor up to 6 cycles. Patients whose disease has not progressed after four cycles of platinum-basedchemotherapy may receive pemetrexed maintenance therapy (pemetrexed 500 mg/m2 on Day 1 ofevery 21-day cycle). Subjects on the chemotherapy arm who had objective radiological progression(by the investigator and confirmed by independent central imaging review) were given the opportunityto begin treatment with TAGRISSO.

The baseline demographic and disease characteristics of the overall study population were: median age62, ≥75 years old (15%), female (64%), White (32%), Asian (65%), never smoker (68%), WHOperformance status 0 or 1 (100%). Fifty-four percent (54%) of patients had extra-thoracic visceralmetastases, including 34% with CNS metastases (identified by CNS lesion site at baseline, medicalhistory, and/or prior surgery, and/or prior radiotherapy to CNS metastases) and 23% with livermetastases. Forty-two percent (42%) of patients had metastatic bone disease.

AURA3 demonstrated a statistically significant improvement in PFS in the patients treated with

TAGRISSO compared to chemotherapy. Efficacy results from AURA3 by investigator assessment aresummarised in Table 8, and the Kaplan-Meier curve for PFS is shown in Figure 11. No statisticallysignificant difference was observed between the treatment arms at the final OS analysis.

Table 8. Efficacy results from AURA3 by investigator assessment

Efficacy parameter TAGRISSO Chemotherapy(N=279) (Pemetrexed/Cisplatin or

Pemetrexed/Carboplatin)(N=140)

Progression-free survival

Number of events (% maturity) 140 (50) 110 (79)

Median PFS, months (95% CI) 10.1 (8.3, 12.3) 4.4 (4.2, 5.6)

HR (95% CI); P-value 0.30 (0.23,0.41); P<0.001

Overall survival (OS)a

Number of deaths (% maturity) 188 (67.4) 93 (66.4)

Median OS, months (95% CI) 26.8 (23.5, 31.5) 22.5 (20.2, 28.8)

HR (95.56% CI); P-value 0.87 (0.67, 1.13); P=0.277

Objective response rateb

Number of responses, response rate 197 44(95% CI) 71% (65, 76) 31% (24, 40)

Odds ratio (95% CI); P-value 5.4 (3.5, 8.5); P<0.001

Duration of response (DoR)b

Median DoR, months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6)

HR=Hazard Ratio; CI=Confidence Interval; NC=Non-calculable; OS=Overall Survival

All efficacy results based on RECIST investigator assessment.a The final analysis of OS was performed at 67% maturity. The CI for the HR has been adjusted for previous interim analyses.

The OS analysis was not adjusted for the potentially confounding effects of crossover (99 [71%] patients on thechemotherapy arm received subsequent osimertinib treatment).b ORR and DoR results by investigator assessment were consistent with those reported via BICR; ORR by BICR assessmentwas 64.9% [95% CI: 59.0, 70.5] on osimertinib and 34.3 % [95% CI: 25.6, 42.8] on chemotherapy; DoR by BICR assessmentwas 11.2 months (95% CI: 8.3, NC) on osimertinib and 3.1 months (95% CI: 2.9, pct. 4.3) on chemotherapy.

Figure 11. Kaplan-Meier curves of progression-free survival as assessed by investigator in

AURA3

A sensitivity analysis of PFS was conducted by a BICR and showed a median PFS of 11.0 monthswith TAGRISSO compared with 4.2 months with chemotherapy. This analysis demonstrated aconsistent treatment effect (HR 0.28; 95% CI: 0.20, 0.38) with that observed by investigatorassessment.

Clinically meaningful improvements in PFS with HRs less than 0.50 in favour of patients receiving

TAGRISSO compared to those receiving chemotherapy were consistently observed in all predefinedsubgroups analysed, including ethnicity, age, gender, smoking history and EGFR mutation (Exon 19deletion and L858R).

CNS metastases efficacy data in AURA3 study

Patients with asymptomatic, stable brain metastases not requiring steroids for at least 4 weeks prior tothe start of study treatment were eligible to be randomised in the study. A BICR assessment of CNSefficacy by RECIST v1.1 in the subgroup of 116/419 (28%) patients identified to have CNSmetastases on a baseline brain scan are summarised in Table 9.

Table 9. CNS efficacy by BICR in patients with CNS metastases on a baseline brain scan in

AURA3

Efficacy parameter TAGRISSO Chemotherapy(Pemetrexed/Cisplatin or

Pemetrexed/Carboplatin)

CNS objective response ratea

CNS response rate % (n/N) 70% (21/30) 31% (5/16)(95% CI) (51, 85) (11%, 59%)

Odds ratio (95% CI); P-value 5.1 (1.4, 21); P=0.015

CNS duration of responseb

Median CNS DoR, months (95% CI) 8.9 (4.3, NC) 5.7 (NC, NC)

CNS disease control rate

CNS disease control rate % (n/N) 87% (65/75) 68% (28/41)(95% CI) (77, 93) (52, 82)

Odds ratio (95% CI); P-value 3 (1.2, 7.9); P=0.021

CNS progression-free survivalc N=75 N=41

Number of events (% maturity) 19 (25) 16 (39)

Median CNS PFS, months (95% CI) 11.7 (10, NC) 5.6 (4.2, 9.7)

HR (95% CI); P-value 0.32 (0.15, 0.69); P=0.004a CNS Objective Response Rate and Duration of Response determined by RECIST v1.1 by CNS BICR in theevaluable for response population (CNS measurable lesions at baseline by BICR) n=30 for TAGRISSO andn=16 for Chemotherapy.b Based on patients with response only; DoR defined as the time from the date of first documented response(complete response or partial response) until progression or death event; DCR defined as the proportion ofpatients with response (complete response or partial response), or stable disease ≥6 weeks.c CNS Progression Free Survival determined by RECIST v1.1 by CNS BICR in the full analysis set population(CNS measurable and non-measurable lesions at baseline by BICR) n=75 for TAGRISSO and n=41 for

Chemotherapy.

A HR <1 favours TAGRISSO.

A pre-specified PFS subgroup analysis based on CNS metastases status at study entry was performedin AURA3 and is shown in Figure 12.

Figure 12. Overall PFS by investigator assessment by CNS metastases status at study entry,

Kaplan-Meier plot (full analysis set) in AURA3

AURA3 demonstrated a statistically significant improvement in PFS for patients receiving

TAGRISSO compared to those receiving chemotherapy irrespective of CNS metastases status at studyentry.

Patient-reported outcomes

Patient-reported symptoms and HRQL were electronically collected using the EORTC QLQ-C30 andits lung cancer module (EORTC QLQ-LC13). The LC13 was initially administered once a week forthe first 6 weeks, then every 3 weeks before and after progression. The C30 was assessed every6 weeks before and after progression.

Key lung cancer symptoms analysis

TAGRISSO improved patient-reported lung cancer symptoms compared to chemotherapy bydemonstrating a statistically significant difference in mean change from baseline versus chemotherapyduring the overall time period from randomisation until 6 months for 5 pre-specified primary PROsymptoms (appetite loss, cough, chest pain, dyspnoea, and fatigue) as shown in Table 10.

Table 10. Mixed Model Repeated Measures - Key lung cancer symptoms - mean change frombaseline in TAGRISSO patients compared with chemotherapy

Appetite Loss Cough Chest Pain Dyspnoea Fatigue

Arms TAGRISS Chemo TAGRISS Chemo TAGRISS Chemo TAGRISS Chemo TAGRISS Chemo

O - O - O - O - O -(279) therapy (279) therapy (279) therapy (279) therapy (279) therapy(140) (140) (140) (140) (140)

N 239 97 228 113 228 113 228 113 239 97

Adj Mean -5.51 2.73 -12.22 -6.69 -5.15 0.22 -5.61 1.48 -5.68 4.71

Estimated -8.24 -5.53 -5.36 -7.09 -10.39

Differenc (-12.88, 3.60) (-8.89, -2.17) (-8.20, -2.53) (-9.86, -4.33) (-14.55, -6.23)e(95%CI)p-value p<0.001 p=0.001 p<0.001 p<0.001 p<0.001

Adjusted mean and estimated differences obtained from a Mixed Model Repeated Measures (MMRM) analysis. The model included patient,treatment, visit, treatment-by-visit interaction, baseline symptom score, and baseline symptom score-by-visit interaction and used anunstructured covariance matrix.

HRQL and physical functioning improvement analysis

Patients on TAGRISSO had significantly greater chances of achieving a clinically meaningfulimprovement of greater than or equal to 10 points on the global health status and physical functioningof the EORTC-C30 questionnaire compared with chemotherapy during the study period Odds Ratio(OR) global health status: 2.11, (95% CI: 1.24, 3.67, p=0.007); OR physical functioning 2.79 (95%

CI: 1.50, 5.46, p=0.002).

Pre-treated T790M-positive NSCLC patients - AURAex and AURA2

Two single-arm, open-label clinical studies, AURAex (Phase 2 Extension cohort, (n=201)) and

AURA2 (n=210) were conducted in patients with EGFR T790M mutation-positive lung cancer whohave progressed on one or more prior systemic therapies, including an EGFR TKI. All patients wererequired to have EGFR T790M mutation-positive NSCLC identified by the cobas EGFR mutation testperformed in a central laboratory prior to treatment. The T790M mutation status was also assessedretrospectively using ctDNA extracted from a plasma sample taken during screening. All patientsreceived TAGRISSO at a dose of 80 mg once daily. The primary efficacy outcome measure of thesetwo studies was ORR according to RECIST v1.1 as evaluated by a BICR. Secondary efficacy outcomemeasures included DoR and PFS.

Baseline characteristics of the overall study population (AURAex and AURA2) were as follows:

median age 63 years, 13% of patients were ≥75 years old, female (68%), White (36%), Asian (60%).

All patients received at least one prior line of therapy. Thirty-one percent (31%) (N=129) had received1 prior line of therapy (EGFR-TKI treatment only), 69% (N=282) had received 2 or more prior lines.

Seventy-two percent (72%) of patients were never smokers, 100% of patients had a WHOperformance status of 0 or 1. Fifty-nine percent (59%) of patients had extra-thoracic visceralmetastasis including 39% with CNS metastases (identified by CNS lesion site at baseline, medicalhistory, and/or prior surgery and/or prior radiotherapy to CNS metastases) and 29% with livermetastases. Forty-seven percent (47%) of patients had metastatic bone disease. The median duration offollow up for PFS was 12.6 months.

In the 411 pre-treated EGFR T790M mutation-positive patients, the total ORR by BICR was 66%(95% CI: 61, 71). In patients with a confirmed response by BICR, the median DoR was 12.5 months(95% CI: 11.1, NE). The ORR by BICR in AURAex was 62% (95% CI: 55, 68) and 70% (95% CI:

63, 77) in AURA2. The median PFS was 11.0 months (95% CI: 9.6, 12.4).

Objective response rates by BICR above 50% were observed in all predefined subgroups analysed,including line of therapy, ethnicity, age and region.

In the evaluable for response population, 85% (223/262) had documentation of response at the time ofthe first scan (6 weeks); 94% (247/262) had documentation of response at the time of the second scan(12 weeks).

CNS metastases efficacy data in Phase 2 studies (AURAex and AURA2)

A BICR assessment of CNS efficacy by RECIST v 1.1 was performed in a subgroup of 50 (out of 411)patients identified to have measurable CNS metastases on a baseline brain scan. A CNS ORR of 54%(27/50 patients; 95% CI: 39.3, 68.2) was observed with 12% of these responses being completeresponses.

Clinical studies have not been conducted in patients with de novo EGFR T790M mutation-positive

The European Medicines Agency has waived the obligation to submit the results of studies with

TAGRISSO in all subsets of the paediatric population in NSCLC (see section 4.2 for information onpaediatric use).

Osimertinib pharmacokinetic parameters have been characterised in healthy subjects and NSCLCpatients. Based on population pharmacokinetic analysis, osimertinib apparent plasma clearance is14.3 L/h, apparent volume of distribution is 918 L and terminal half-life of approximately 44 hours.

The pharmacokinetics in patients treated with osimertinib in combination with pemetrexed andplatinum-based chemotherapy are similar to those in patients treated with osimertinib monotherapy.

The AUC and Cmax increased dose proportionally over 20 to 240 mg dose range. Administration ofosimertinib once daily results in approximately 3-fold accumulation with steady-state exposuresachieved by 15 days of dosing. At steady-state, circulating plasma concentrations are typicallymaintained within a 1.6-fold range over the 24-hour dosing interval.

Following oral administration of TAGRISSO, peak plasma concentrations of osimertinib wereachieved with a median (min-max) tmax of 6 (3-24) hours, with several peaks observed over the first 24hours in some patients. The absolute bioavailability of TAGRISSO is 70% (90% CI 67, 73). Based ona clinical pharmacokinetic study in patients at 80 mg, food does not alter osimertinib bioavailability toa clinically meaningful extent (AUC increase by 6% (90% CI -5, 19) and Cmax decrease by 7% (90%

CI -19, 6)). In healthy volunteers administered an 80 mg tablet where gastric pH was elevated bydosing of omeprazole for 5 days, osimertinib exposure was not affected (AUC and Cmax increase by7% and 2%, respectively) with the 90% CI for exposure ratio contained within the 80-125% limit.

Population estimated mean volume of distribution at steady-state (Vss/F) of osimertinib is 918 Lindicating extensive distribution into tissue. In vitro plasma protein binding of osimertinib is 94.7%(5.3% free). Osimertinib has also been demonstrated to bind covalently to rat and human plasmaproteins, human serum albumin and rat and human hepatocytes.

In vitro studies indicate that osimertinib is metabolised predominantly by CYP3A4, and CYP3A5.

However, with current available data, alternative metabolic pathways cannot be fully ruled out. Basedon in vitro studies, 2 pharmacologically active metabolites (AZ7550 and AZ5104) have subsequentlybeen identified in the plasma of preclinical species and in humans after oral dosing with osimertinib;

AZ7550 showed a similar pharmacological profile to TAGRISSO while AZ5104 showed greaterpotency across both mutant and wild-type EGFR. Both metabolites appeared slowly in plasma afteradministration of TAGRISSO to patients, with a median (min-max) tmax of 24 (4-72) and 24 (6-72)hours, respectively. In human plasma, parent osimertinib accounted for 0.8%, with the 2 metabolitescontributing 0.08% and 0.07% of the total radioactivity with the majority of the radioactivity beingcovalently bound to plasma proteins. The geometric mean exposure of both AZ5104 and AZ7550,based on AUC, was approximately 10% each of the exposure of osimertinib at steady-state.

The main metabolic pathway of osimertinib was oxidation and dealkylation. At least 12 componentswere observed in the pooled urine and faecal samples in humans with 5 components accounting for>1% of the dose of which unchanged osimertinib, AZ5104 and AZ7550, accounted for approximately1.9, 6.6 and 2.7% of the dose while a cysteinyl adduct (M21) and an unknown metabolite (M25)accounted for 1.5% and 1.9% of the dose, respectively.

Based on in vitro studies, osimertinib is a competitive inhibitor of CYP 3A4/5 but not CYP1A2, 2A6,2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinically relevant concentrations. Based on in vitro studies,osimertinib is not an inhibitor of UGT1A1 and UGT2B7 at clinically relevant concentrationshepatically. Intestinal inhibition of UGT1A1 is possible but the clinical impact is unknown.

Following a single oral dose of 20 mg, 67.8% of the dose was recovered in faeces (1.2% as parent)while 14.2% of the administered dose (0.8% as parent) was found in urine by 84 days of samplecollection. Unchanged osimertinib accounted for approximately 2% of the elimination with 0.8% inurine and 1.2% in faeces.

Interactions with transport proteins

In vitro studies have shown that osimertinib is not a substrate of OATP1B1 and OATP1B3. In vitro,osimertinib does not inhibit OAT1, OAT3, OATP1B1, OATP1B3, MATE1, OCT2 and MATE2K atclinically relevant concentrations.

Based on in vitro studies osimertinib is a substrate of P-gp and BCRP but at clinical doses, clinicallyrelevant interactions are unlikely. Based on in vitro data, osimertinib is an inhibitor of BCRP and P-gp(see section 4.5).

In a population based pharmacokinetic analyses (n=1367), no clinically significant relationships wereidentified between predicted steady-state exposure (AUCss) and patient’s age (range: 25 to 91 years),gender (65% female), ethnicity (including White, Asian, Japanese, Chinese and non-Asian-non-Whitepatients), line of therapy and smoking status (n=34 current smokers, n=419 former smokers).

Population PK analysis indicated that body weight was a significant covariate with a less than 20%change in osimertinib AUCss expected across a body weight range of 88 kg to 43 kg respectively (95%to 5% quantiles) when compared to the AUCss for the median body weight of 61 kg. Taking theextremes of body weight into consideration, from <43 kg to >88 kg, AZ5104 metabolite ratios rangedfrom 11.8% to 9.6% while for AZ7550 it ranged from 12.8% to 8.1%, respectively. Based onpopulation PK analysis, serum albumin was identified as a significant covariate with a <30% changein osimertinib AUCss expected across the albumin range of 29 to 46 g/L respectively (95% to 5%quantiles) when compared to the AUCss for the median baseline albumin of 39 g/L. These exposurechanges due to body weight or baseline albumin differences are not considered clinically relevant.

Osimertinib is eliminated mainly via the liver. In a clinical study, patients with different types ofadvanced solid tumours and with mild hepatic impairment (Child Pugh A, mean score=5.3, n=7) ormoderate hepatic impairment (Child Pugh B, mean score=8.2, n=5) had no increase in exposurecompared to patients with normal hepatic function (n=10) after a single 80 mg dose of TAGRISSO.

The geometric mean ratio (90% CI) of osimertinib AUC and Cmax was 63.3% (47.3, 84.5) and 51.4%(36.6, 72.3) in patients with mild hepatic impairment and 68.4% (49.6, 94.2) and 60.7% (41.6, 88.6) inpatients with moderate hepatic impairment; for the metabolite AZ5104 the AUC and Cmax were 66.5%(43.4, 101.9) and 66.3% (45.3, 96.9) in patients with mild hepatic impairment and 50.9% (31.7, 81.6)and 44.0% (28.9, 67.1) in patients with moderate hepatic impairment, compared to the exposure inpatients with normal hepatic function. Based on population PK analysis, there was no relationshipbetween markers of hepatic function (ALT, AST, bilirubin) and osimertinib exposure. The hepaticimpairment marker serum albumin showed an effect on the PK of osimertinib. Clinical studies thatwere conducted excluded patients with AST or ALT >2.5x upper limit of normal (ULN), or if due tounderlying malignancy, >5.0x ULN or with total bilirubin >1.5x ULN. Based on a pharmacokineticanalysis of 134 patients with mild hepatic impairment, 8 patients with moderate hepatic impairmentand 1216 patients with normal hepatic function osimertinib exposures were similar. There are no dataavailable on patients with severe hepatic impairment (see section 4.2).

In a clinical study, patients with severe renal impairment (CLcr 15 to less than 30 mL/min; n=7)compared to patients with normal renal function (CLcr greater than or equal to 90 mL/min; n=8) aftera single 80 mg oral dose of TAGRISSO showed a 1.85-fold increase in AUC (90% CI; 0.94, 3.64) anda 1.19-fold increase in Cmax (90% CI: 0.69, 2.07). Furthermore, based on a population pharmacokineticanalysis of 593 patients with mild renal impairment (CLcr 60 to less than 90 mL/min), 254 patientswith moderate renal impairment (CLcr 30 to less than 60 mL/min), 5 patients with severe renalimpairment (CLcr 15 to less than 30 mL/min) and 502 patients with normal renal function (greaterthan or equal to 90 mL/min), osimertinib exposures were similar. Patients with CLcr less than or equalto 10 mL/min were not included in the clinical studies.

PET images following administration of microdoses of [11C]osimertinib in EGFR mutation-positive

NSCLC patients with brain metastases (n=4) and healthy volunteers (n=7) demonstrated that the brainto plasma ratio (Kp) was similar and that [11C]osimertinib crossed the blood brain barrier rapidly andwas homogeneously distributed across all regions of the brain in both patients and healthy volunteers.

The main findings observed in repeat dose toxicity studies in rats and dogs comprised atrophic,inflammatory and/or degenerative changes affecting the epithelia of the cornea (accompanied bycorneal translucencies and opacities in dogs at ophthalmology examination), GI tract (includingtongue), skin, and male and female reproductive tracts with secondary changes in spleen. Thesefindings occurred at plasma concentrations that were below those seen in patients at the 80 mgtherapeutic dose. The findings present following 1 month of dosing were largely reversible within1 month of cessation of dosing with the exception of partial recovery for some of the corneal changes.

Lens fibre degeneration was found in the 104-week carcinogenicity rat study at exposures 0.2 timesthe human AUC, at the recommended clinical dose of 80 mg once a day. Lens opacities were firstnoted from week 52 of this study and showed a gradual increase in incidence and severity withincreased duration of dosing. The clinical relevance of this finding cannot be ruled out.

Osimertinib penetrated the intact blood-brain barrier of the cynomolgus monkey (intravenous dosing),rat and mouse (oral administration).

Non-clinical data indicate that osimertinib and its metabolite (AZ5104) inhibit the h-ERG channel, and

QTc prolonging effect cannot be excluded.

Osimertinib did not cause genetic damage in in vitro and in vivo assays. Osimertinib showed nocarcinogenic potential when administered orally to Tg rasH2 transgenic mice for 26 weeks. Anincreased incidence of proliferative vascular lesions (angiomatous hyperplasia and haemangioma) inthe mesenteric lymph node was observed in the rat 104-week carcinogenicity study at exposures0.2 times the AUC at the recommended clinical dose of 80 mg once daily, and is unlikely to berelevant for humans.

Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for ≥1 monthand there was a reduction in male fertility in rats following exposure to osimertinib for 3 months.

These findings were seen at clinically relevant plasma concentrations. Pathology findings in the testesseen following 1 month dosing were reversible in rats; however, a definitive statement on reversibilityof these lesions in dogs cannot be made.

Based on studies in animals, female fertility may be impaired by treatment with osimertinib. In repeatdose toxicity studies, an increased incidence of anoestrus, corpora lutea degeneration in the ovariesand epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for ≥1 monthat clinically relevant plasma concentrations. Findings in the ovaries seen following 1 month dosingwere reversible. In a female fertility study in rats, administration of osimertinib at 20 mg/kg/day(approximately equal to the recommended daily clinical dose of 80 mg) had no effects on oestruscycling or the number of females becoming pregnant, but caused early embryonic deaths. Thesefindings showed evidence of reversibility following a 1 month off-dose.

In a modified embryofoetal development study in the rat, osimertinib caused embryolethality whenadministered to pregnant rats prior to embryonic implantation. These effects were seen at a maternallytolerated dose of 20 mg/kg where exposure was equivalent to the human exposure at the recommendeddose of 80 mg daily (based on total AUC). Exposure at doses of 20 mg/kg and above duringorganogenesis caused reduced foetal weights but no adverse effects on external or visceral foetalmorphology. When osimertinib was administered to pregnant female rats throughout gestation andthen through early lactation, there was demonstrable exposure to osimertinib and its metabolites insuckling pups plus a reduction in pup survival and poor pup growth (at doses of 20 mg/kg and above).

Mannitol

Microcrystalline cellulose

Low-substituted hydroxypropyl cellulose

Sodium stearyl fumarate

Polyvinyl alcohol

Titanium dioxide (E 171)

Macrogol 3350

Talc

Yellow iron oxide (E 172)

Red iron oxide (E 172)

Black iron oxide (E 172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Al/Al perforated unit dose blisters. Cartons of 30 x 1 tablets (3 blisters).

Al/Al perforated unit dose blisters. Cartons of 28 x 1 tablets (4 blisters).

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/16/1086/001 40 mg 30 film-coated tablets

EU/1/16/1086/002 80 mg 30 film-coated tablets

EU/1/16/1086/003 40 mg 28 film-coated tablets

EU/1/16/1086/004 80 mg 28 film-coated tablets

Date of first authorisation: 2 February 2016

Date of latest renewal: 24 March 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.